Altered white matter volumes in first-episode depression: Evidence from cross-sectional and longitudinal voxel-based analyses.

BACKGROUND: Major depressive disorder (MDD) is accompanied by atypical brain structure affecting grey and white matter from the early stages. Neuroimaging studies of first-episode depression (FED) have provided evidence on this regard, but most of the studies are cross-sectional. The aim of this longitudinal study was to test potential changes in grey matter (GM) and white matter (WM) volumes in FED. METHODS: Thirty-three untreated FED patients (DSM-IV criteria) and 33 healthy controls (HC) underwent a 3T structural magnetic resonance imaging (sMRI) at baseline and after 2 years. Depressive symptoms were assessed at baseline and throughout the study with the 17-item Hamilton Depressive Rating Scale (HDRS-17). Recurrences of FED patients were also collected along the follow-up. To analyze GM and WM differences, whole-brain voxel-based morphometry (VBM, SPM12) was employed (FWE corrected). RESULTS: FED patients showed significant reductions compared to HC in WM volumes of prefrontal cortex (left anterior corona radiata). No differences were found in GM volumes. Full factorial longitudinal analysis of the whole sample revealed no significant effect in GM nor in WM, while the full factorial longitudinal analysis comparing recurrent and non-recurrent patients showed increments in WM volumes of left posterior corona radiata and right posterior thalamic radiation in the recurrent group. LIMITATIONS: Limited sample size, especially in the follow-up. CONCLUSIONS: The present findings provided some new evidence of the role of white matter alterations in the early stages of MDD and in the progression of the illness.

Cognitive predictors of illness course at 12 months after first-episode of depression.

Major Depressive Disorder (MDD) entails cognitive dysfunction in many cognitive domains, but it is still uncertain whether such deficits are present in the early stages. The purpose of the study is to determine the cognitive performance in first episode depression (FED) exploring the presence of different cognitive profiles, and the role of cognition in FED at baseline and long-term. Ninety subjects (18-50 years) were included, 50 patients with a FED and 40 healthy controls. Participants were assessed with a neuropsychological battery, covering language, attention, verbal memory, processing speed and executive domains. Neuropsychological group comparisons were performed with MANOVAs. A hierarchical cluster analysis was run to identify clusters of patients with similar neuropsychological performance. Two generalized linear models were built to predict baseline HDRS-17 and changes at 12 months. Patients performed significantly worse than healthy controls in language, attention/working memory, verbal memory, processing speed and executive functioning, with moderate to large effect sizes (0.5 - 1). Two clusters were found: cognitively preserved patients (n=37) and cognitively impaired patients (n=13). Large effect sizes of cognitive impairment in FED were observed between the two cognitive clusters (preserved and impaired). Depressive symptoms at baseline were predicted by verbal memory (p=0.003), while 12-month changes were predicted by executive function (p=0.041) and language (p=0.037). Cognitive performance predicted depressive symptoms at baseline and at follow-up, pointing to the usefulness of cognitive assessment even at the commencement of the illness.

Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis.

BACKGROUND: Abnormalities in the hippocampus have been implicated in the pathophysiology of psychosis. However, it is still unclear whether certain abnormalities are a pre-existing vulnerability factor, a sign of disease progression or a consequence of environmental factors. We hypothesized that first-episode psychosis patients who progress to schizophrenia after one year of follow up will display greater volumetric and morphological changes from the very beginning of the disorder. METHODS: We studied the hippocampus of 41 patients with a first-episode psychosis and 41 matched healthy controls. MRI was performed at the time of the inclusion in the study. After one year, the whole sample was reevaluated and divided in two groups depending on the diagnoses (schizophrenia vs. non-schizophrenia). RESULTS: Patients who progressed to schizophrenia showed a significantly smaller left hippocampus volume than control group and no-schizophrenia group (F=3.54; df=2, 77; P=0.03). We also found significant differences in the morphology of the anterior hippocampus (CA1) of patients with first-episode psychosis who developed schizophrenia compared with patients who did not. CONCLUSIONS: These results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis.

A preliminary longitudinal study on the cognitive and functional outcome of bipolar excellent lithium responders.

BACKGROUND: Neurocognitive dysfunction in bipolar disorder represents a possible marker of underlying pathophysiology, but to date, most studies are cross-sectional and heterogeneous with regard to pharmacological treatments. In the present study we investigated the 6-year cognitive and functional outcome of a sample of euthymic excellent lithium responders (ELR). METHOD: A total sample of twenty subjects was assessed at baseline and 6years later: ten diagnosed of bipolar disorder according to DSM-IV criteria and ten healthy matched controls. The sample size was enough to find statistical differences between groups, with a statistical power of 0.8. Bipolar patients were on lithium treatment during all this follow-up period and fulfilled ELR criteria as measured by the Alda scale. A neuropsychological test battery tapping into the main cognitive domains was used at baseline and at after 6-year of follow-up. Functional outcome was evaluated by means of the Functioning Assessment Short Test at study endpoint. RESULTS: Repeated measures multivariate analyses of variance showed that bipolar patients were cognitively impaired in the executive functioning, inhibition, processing speed and verbal memory domains (p<0.03) compared to controls and such deficits were stable over time. Longer duration of illness and lower psychosocial outcome were significantly related to cognitive impairment (p<0.05). CONCLUSIONS: Cognitive dysfunction was present even in euthymic ELR. These deficits remain stable over the long term, and are basically associated with greater symptoms and poorer psychosocial adjustment.

Volumetric MRI study of the habenula in first episode, recurrent and chronic major depression.

The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD.

Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression.

BACKGROUND: Although white-matter abnormalities have been reported in middle-aged patients with major depressive disorder (MDD), few data are available on treatment-resistant MDD and the influence of relevant variables related to clinical burden of illness is far from being well established. METHOD: The present study examined white-matter microstructure in a sample of 52 patients with MDD in different stages (treatment-resistant/chronic MDD, n = 18; remitted-recurrent MDD, n = 15; first-episode MDD, n = 19) and 17 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. Groups were comparable in age and gender distribution, and results were corrected for familywise error (FWE) rate. RESULTS: Widespread significant reductions of fractional anisotropy (FA) - including the cingulum, corpus callosum, superior and inferior longitudinal fascicule - were evident in treatment-resistant/chronic MDD compared with first-episode MDD and controls (p < 0.05, FWE-corrected). Decreased FA was observed within the ventromedial prefrontal region in treatment-resistant/chronic MDD even when compared with the remitted-recurrent MDD group (p < 0.05, FWE-corrected). Longer duration of illness (ß = -0.49, p = 0.04) and higher depression severity (at a trend level: ß = -0.26, p = 0.06) predicted lower FA in linear multiple regression analysis at the whole-brain level. The number of previous episodes and severity of symptoms were significant predictors when focused on the ventromedial prefrontal area (ß = -0.28, p = 0.04; and ß = -0.29, p = 0.03, respectively). Medication effects were controlled for in the analyses and results remained unaltered. CONCLUSIONS: Our findings support the notion that disruptions of white-matter microstructure, particularly in fronto-limbic networks, are associated with resistance to treatment and higher current and past burden of depression.

Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study.

BACKGROUND: Previous cross-sectional studies report that cognitive impairment is associated with poor psychosocial functioning in euthymic bipolar patients. There is a lack of long-term studies to determine the course of cognitive impairment and its impact on functional outcome. Method A total of 54 subjects were assessed at baseline and 6 years later; 28 had DSM-IV TR bipolar I or II disorder (recruited, at baseline, from a Lithium Clinic Program) and 26 were healthy matched controls. They were all assessed with a cognitive battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory) twice over a 6-year follow-up period. All patients were euthymic (Hamilton Rating Scale for Depression score lower than 8 and Young mania rating scale score lower than 6) for at least 3 months before both evaluations. At the end of follow-up, psychosocial functioning was also evaluated by means of the Functioning Assessment Short Test. RESULTS: Repeated-measures multivariate analysis of covariance showed that there were main effects of group in the executive domain, in the inhibition domain, in the processing speed domain, and in the verbal memory domain (p<0.04). Among the clinical factors, only longer illness duration was significantly related to slow processing (p=0.01), whereas strong relationships were observed between impoverished cognition along time and poorer psychosocial functioning (p<0.05). CONCLUSIONS: Executive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients.

Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment.

BACKGROUND AND PURPOSE: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed ß-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.

Neuropsychological profile in bipolar disorder: a preliminary study of monotherapy lithium-treated euthymic bipolar patients evaluated at a 2-year interval.

OBJECTIVE: To investigate the cognitive impairment of a sample of euthymic bipolar patients treated with lithium monotherapy at baseline in a 2-year longitudinal study. METHOD: Fifteen DSM-IV-TR bipolar out-patients and 15 healthy-matched controls were cognitively assessed twice over a 2-year follow-up. All patients underwent lithium monotherapy on the first evaluation, and they were euthymic in both evaluations. Cognitive assessment was performed by means of a neuropsychological test battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory). RESULTS: Repeated measures multivariate analysis of variance showed that the bipolar disorder group was cognitively impaired in the executive domain, attention and processing speed, and such deficits were maintained over time. CONCLUSION: Our results showed that executive dysfunction is the main long-term neuropsychological deficit of bipolar disorder. Also, the persistence of these deficits did not seem to be influenced by any clinical or pharmacological variables.

No brain perfusion impairment at long-term follow-up in elderly patients treated with electroconvulsive therapy for major depression.

No functional neuroimaging study has previously assessed the long-term effects of electroconvulsive therapy (ECT) on brain perfusion. In this study, long-term follow-up brain perfusion in elderly patients treated with ECT for severe unipolar major depression was assessed. In 14 elderly major depressed patients who were ECT remitters, 22 elderly major depressed patients who were pharmacological treatment remitters and 25 age- and sex-matched healthy controls, a medication-free brain 9mTc-HMPAO-SPECT was performed after a minimum period of 12 months of euthymia and, in the case of the ECT remitters, at least 12 months after the last ECT session. Brain perfusion ratios in major depressed patients administered ECT were similar to those in major depressed patients receiving pharmacological treatment and in control subjects. This result suggests that elderly patients given ECT for severe unipolar major depression do not suffer brain perfusion abnormalities at long-term follow-up. Our study adds new evidence in favor of the safety of the ECT, particularly in elderly subjects.

['Tower of London': mental planning, validity and the ceiling effect]. / 'Torre de Londres': planificación mental, validez y efecto techo.

INTRODUCTION: The Tower of London (TL) is a neuropsychological test that is used to evaluate the capacity for planning. Different versions of the TL exist, including the classical version that presents certain psychometric problems (for example, the ceiling effect). AIMS: The aim of this study was to propose a new method of administering and correcting the classical version of the TL, thus increasing the mental resolution of the planning task through instruction, and varying the system of scoring in order to obtain a wider range of scores. PATIENTS AND METHODS: Two versions of the TL were administered to two independent, counterbalanced groups. One of them was the one designed by Krikorian and the other was the one proposed for this study. To compare the two versions, Porteus mazes were administered in each group as a criterion variable in the study of correlations. RESULTS: Both versions correlate with the Porteus mazes in a similar fashion. The variances found in each group are statistically different and the coefficient of covariance is clearly wider in the group that received the version proposed in this study. CONCLUSIONS: Changing the instruction for the mental resolution of planning tasks does not appear to alter the TL. The changes introduced in the correction and the system of scoring of the version proposed for this study present wider variance, which means that the ceiling effect has been overcome.

Residual cognitive impairment in late-life depression after a 12-month period follow-up.

OBJECTIVES: This study investigated cognitive impairment in late-life depression in a follow-up design. The main objective was to assess the most important cognitive domains implicated in late-life depression, in patients who underwent pharmacological treatment, in the acute phase and twelve months after. METHODS: Neuropsychological and clinical data were used from the baseline of patients and controls, to determine the cognitive impairment in the acute phase. Patients repeated the neuropsychological assessment at twelve months. RESULTS: There were significant differences between patients and controls at baseline. But in the patients there was no change over twelve months. There were no differences between remitted and non-remitted patients on neuropsychological scores. CONCLUSIONS: The cognitive impairment seen in the elderly depressed patients seems to be a trait characteristic of this mental disease, even when the depressive episode has remitted.

Residual symptoms in elderly major depression remitters.

OBJECTIVE: To assess residual symptoms in severe geriatric major depression in remission, and to determine baseline clinical and sociodemographic predictors of residual symptoms in remitters. METHOD: A total of 108 elderly patients with unipolar major depression were evaluated and treated naturalistically for 9 months so as to record the predictors of residual symptoms in remitters. In order to reduce the likelihood of confusing residual symptoms with normal effects of age, 30 control subjects were also monitored. RESULTS: Seventy-nine patients (73.1%) were considered remitters and 82.3% of remitters showed residual symptoms. Medical burden, chronic stress and subjective social support were the only variables which predicted the severity of residual symptoms in remitters. CONCLUSION: Residual symptoms in elderly patients with major depression in remission should not only be attributed exclusively to intrinsic factors of the illness or the age of the individual patient, but also to external factors.

[Assessment of frontal functions in psychiatric patients during maintenance electroconvulsive therapy]. / Evaluación de las funciones frontales en pacientes psiquiátricos durante el tratamiento con terapia electroconvulsiva de mantenimiento.

INTRODUCTION: Previous studies on adverse cognitive effects of electroconvulsive therapy (ECT) have not found any significant alteration of the frontal functions after an acute treatment course. This study aims to assess frontal executive functions in psychiatric patients during maintenance electroconvulsive therapy (M-ECT). SUBJECTS AND METHODS: Thirty two patients treated with M-ECT and 29 psychiatric patients never treated with ECT were evaluated with neuropsychological tests that assessed the following frontal functions: work memory, planning, cognitive flexibility, attention, visuomotor velocity, verbal abstract reasoning and phonetic verbal fluency. RESULTS: Multivariate global analysis did not detect significant frontal function tests differences between both groups. The M-ECT group only scored significantly lower on the FAS test, a test that measures phonetic verbal fluency. A significant correlation between number of previous ECT sessions and performance in the FAS was found. CONCLUSIONS: The M-ECT patient group presented a phonetic verbal fluency alteration that may also be associated to the previous number of ECT sessions. No significant differences in the other frontal functions were detected.

[Selective alteration of the declarative memory systems in patients treated with a high number of electroconvulsive therapy sessions]. / Alteracion selectiva de los sistemas declarativos de memoria en los pacientes tratados con un elevado numero de sesiones de terapia electroconvulsiva.

INTRODUCTION: The reversible electrochemical effects of electroconvulsive therapy (ECT) on specific areas of the brain enable the neuroanatomical bases of some cognitive functions to be studied. In research carried out on memory systems, a selective alteration of the declarative ones has been observed after treatment with ECT. Little work has been done to explore the differential alteration of the memory subsystems in patients with a high number of ECT sessions. AIM. To study the declarative and non declarative memory system in psychiatric patients submitted to maintenance ECT treatment, with a high number of previous ECT sessions. PATIENTS AND METHODS: 20 patients submitted to treatment with ECT (10 diagnosed as having depression and 10 with schizophrenia) and 20 controls, who were paired by age, sex and psychopathological diagnosis. For the evaluation of the declarative memory system, the Wechsler Memory Scale (WMS) logical memory test was used. The Hanoi Tower procedural test was employed to evaluate the non declarative system. RESULTS: Patients treated with ECT performed worse in the WMS logical memory test, but this was only significant in patients diagnosed as suffering from depression. No significant differences were observed in the Hanoi Tower test. CONCLUSIONS: A selective alteration of the declarative systems was observed in patients who had been treated with a high number of ECT sessions, while the non declarative memory systems remain unaffected.

[Frontal lobe involvement in elderly major depression]. / Implicación del lóbulo frontal en la depresión mayor senil.

INTRODUCTION: It is acknowledged that major depression (MD) entails alterations in moods, physiological dysfunctions and cognitive dysfunctions. The neuropsychological profile of this mental disorder, however, is still unknown. Furthermore, in the nosological delimitation of depressive disorders there are different categories, which makes it still more difficult to establish the cognitive dysfunction of MD. Over the last few years, a great deal of effort has been aimed at establishing a neuropsychological profile of elderly major depression (EMD) as a distinct depressive disorder, since it also involves other variables such as the course and response to pharmacological treatment. AIMS. The objective of this study is to review the present state of the cognitive deficits in EMD and their possible neurobiological correlates. METHOD: From a search in the Medline database using the keywords elderly major depressive disorders , cognitive function , frontal lobes and prefrontal area , we selected studies that had been conducted over the last 10 years. CONCLUSIONS: Recent studies have found mnemonic deficits, together with an executive dysfunction in EMD. Bearing in mind the interactions between affection, motivation and cognitive function enables us to better understand the involvement of the fronto subcortical pathways in this disorder. Moreover, future research should centre on the pathways that connect the frontal lobes and, more specifically, those between the prefrontal dorsolateral area and practically the rest of the brain, since, from what can be observed in the findings obtained, the executive dysfunction could be due to a brain connection disorder