Influence of family history of major depression, bipolar disorder, and suicide on clinical features in patients with major depression and bipolar disorder

The extent to which a family history of mood disorders and suicide could impact on clinical features of patients suffering from major depression (MD) and bipolar disorder (BD) has received relatively little attention so far. The aim of the present work is, therefore, to assess the clinical implications of the presence of at least one first- and/or second-degree relative with a history of MD, BD and suicide in a large sample of patients with MD or BD. One thousand one hundred and fifty-seven subjects with MD and 686 subjects with BD were recruited within the context of two large projects. The impact of a family history of MD, BD, and suicide—considered both separately and together—on clinical and socio-demographic variables was investigated. A family history of MD, BD, and suicide was more common in BD patients than in MD patients. A positive family history of mood disorders and/or suicide as well as a positive family history of MD and BD separately considered, but not a positive history of suicide alone, were significantly associated with a comorbidity with several anxiety disorders and inversely associated with age of onset. The clinical implications as well as the limitations of our findings are discussed.     

Evidence for homogeneity of major depression and bipolar affective disorder

This study compared the morbidity risk for affective disorder in relatives of probands who had bipolar (BP) or major depression (UP). Other risk factors were also evaluated. 112 consecutively admitted inpatients yielded 621 relatives with diagnostic information based on either the Renard diagnostic interview, hospital records or information from at least two reliable relatives using the Feighner diagnostic criteria. Similar age corrected morbid risk estimates were found for family members of UP and BP probands of 0.243 and 0.246. There was a 50% increase in morbidity risk for women in all three generations but no relationship to the diagnosis of the proband. A proportional hazards (life table) analysis demonstrated that probands with onset prior to age 40 had relatives with younger onset and higher risk. None of the analyses, including logistic regression and proportional hazards, differentiated UP from BP illness.     

Patterns of memory impairment in bipolar disorder and unipolar major depression

Unipolar and bipolar depression are known to exert detrimental effects on learning and memory processes. However, few comparisons have been undertaken between bipolar and unipolar patients with comparable illness histories, and predictors of impairment are not well understood. Adult outpatients with unipolar major depressive illness (UP, n = 30) and bipolar disorder (BP, n = 30), group-matched for illness duration and severity of depressive symptomatology (16% clinically remitted, 42% partially remitted, 42% depressed), and 30 demographically matched controls completed measures of general cognitive functioning and declarative memory. Despite comparable general intellectual abilities, BP and UP patients exhibited significant memory deficits relative to healthy controls. A similar deficit profile was observed in both patient groups, involving poorer verbal recall and recognition. Impairments were not secondary to strategic processing deficits or rapid forgetting. Although depression severity was not associated with neurocognitive performance, number of hospitalizations and family history of mood disorder significantly affected memory function in BP, but not UP, patients. Results suggest qualitatively similar patterns of memory impairment in BP and UP patients, consistent with a primary encoding deficit. These impairments do not appear to be secondary to clinical state, but rather suggest a similar underlying pathophysiology involving medial temporal dysfunction.     

Distinguishing affective depersonalization from anhedonia in major depression and bipolar disorder

Background

Affective depersonalization has received limited attention in the literature, although its conceptualization may have implications in terms of identification of clinical endophenotypes of mood disorders. Thus, this study aims to test the hypothesis that anhedonia and affective depersonalization represent 2 distinct psychopathological dimensions and to investigate their clinical correlates in patients with major depressive disorder (MDD) and bipolar disorder (BD).

Methods

Using a data pool of 258 patients with mood and anxiety disorders, an item response theory-based factor analysis approach was carried out on 16 items derived from 2 clinical instruments developed in the Spectrum Project (the Structured Clinical Interview for Mood Spectrum and the Structured Clinical Interview for Derealization-Depersonalization Spectrum). Clinical correlates of these psychometrically derived dimensions were subsequently investigated in patients with BD or MDD.

Results

Using an item response theory-based factor analysis, a 2-factor solution was identified, accounting overall for the 47.0% of the variance. Patients with BD showed statistically significant higher affective depersonalization factor scores than those with MDD (Z = 2.215, P = .027), whereas there was no between-groups difference in anhedonia scores (Z = 0.825 P = .411). In patients with BD, age of onset of the disease correlated with affective depersonalization factor scores (ρ = −0.330, P = .001) but not with anhedonia factor scores (ρ = −0.097, P = .361).

Conclusions

Affective depersonalization and anhedonia seem to be 2 distinct psychopathological dimensions, although closely related, bearing the opportunity to identify patients with a specific profile for a better clinical and neurobiological definition.     

Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains.

BACKGROUND: Previous studies of postmortem neurochemical markers in severe psychiatric disorders have been carried out on different brain collections, making it difficult to compare results. METHODS: One hundred RNA, protein, and other neurochemical markers were assessed in a single set of 60 postmortem brains (15 each with schizophrenia, bipolar disorder, major depression without psychosis, and unaffected control subjects) in relation to seven neurochemical systems. Quantitative measures of continuous variables for prefrontal, hippocampus, anterior cingulate, superior temporal cortex, or a combination of these were analyzed from published and unpublished studies by 56 research groups. RESULTS: Before correcting for multiple comparisons, 23% of markers (23/100) were abnormal in one or more regions, with most indicating decreased expression. The largest percentage were associated with the developmental/synaptic (10/22) and gamma-aminobutyric acid (GABA; 3/7) systems. Bipolar disorder (20) and schizophrenia (19) had the most abnormalities, with a 65% overlap. When all brain areas were considered together and corrected for multiple comparisons, reelin, parvalbumin, and GAD67 were the most abnormal. CONCLUSIONS: Confirming other studies, the GABA and developmental/synaptic neurochemical systems are promising areas for research on schizophrenia and bipolar disorder. Research should include tissue from both diseases, and additional brain areas should be assessed.     

Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression

Structural abnormalities in frontal, limbic and subcortical regions have been noted in adults with both major depressive disorder (MDD) and bipolar disorder (BD). In the current study, we examined regional brain morphology in youth with MDD and BD as compared to controls. Regional brain volumes were measured in 32 MDD subjects (15.7?±?2.1 years), 14 BD subjects (16.0?±?2.4 years) and 22 healthy controls (16.0?±?2.8 years) using magnetic resonance imaging (MRI). Regions of interest included the hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), caudate, putamen and thalamus. Volumetric differences between groups were significant (F_26,80?=?1.80, p?=?0.02). Post-hoc analyses indicated that individuals with MDD showed reduced left hippocampus volumes (p?=?0.048) as well as right ACC white and gray matter volumes (p?=?0.003; p?=?0.01) compared to controls. BD participants also displayed reduced left hippocampal and right/left putamen volumes compared to controls (p?<?0.001; p?=?0.015; p?=?0.046 respectively). Interestingly, right and left ACC white matter volumes were smaller in MDD than in BD participants (p?=?0.019; p?=?0.045 respectively). No volumetric group differences were observed for the DLPFC and thalamus. Discriminant analysis was able to correctly classify 81.0 % of subjects as having BD or as MDD based on imaging data. Confirmation and extension of our findings requires larger sample sizes. Our findings provide new evidence of distinct, specific regional brain volumetric differences between MDD and BD that may be used to distinguish the two disorders.     

Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia

BACKGROUND: The orbitofrontal cortex is involved in the monitoring of reward and in judgement. Lesion studies and functional neuroimaging investigations implicate this region in affective disorders, and altered neuronal and glial cell composition have been observed in this region in subjects with major depressive disorder (MDD). AIMS: Stereologically based investigation of caudal orbitofrontal cortex (cOFC), in 60 postmortem brains from four groups of 14 subjects each with bipolar disorder (BPD), schizophrenia and MDD. METHODS: Glial cell and neuronal size and density were examined in all subjects using stereological probes such as the nucleator and the optical disector. RESULTS: We found statistical evidence for a neuronal size reduction in BPD in layer 1 (21%, p=0.007) and a trend for a reduction in layer 5 (20%, p=0.05). There was a significant interaction effect of brain hemisphere and group on neuronal size in layer 3 (p=0.001), with evidence for reduced layer 3 neuronal sizes in MDD (30%, p<0.001). We found no evidence for group differences in glial cell size nor for differences in glial or neuronal density. CONCLUSIONS: These findings provide preliminary evidence that neuronal size reduction in cOFC is a component of the pathology of BPD. Overall, the data implicate this cortical region in affective disorders, but provide no evidence for neuronal or glial pathology in this region in schizophrenia.     

Mood symptoms, cognition, and everyday functioning: in major depression, bipolar disorder, and schizophrenia

People with depression, bipolar disorder, and schizophrenia manifest considerable cognitive deficits and impairments in everyday functional outcomes. The severity of current mood symptoms is associated with the severity of cognitive deficits in people with unipolar and bipolar disorder, but impairments are clearly still present in cases with minimal current mood symptoms. In people with schizophrenia, depression is less strongly associated with cognitive deficits on a cross-sectional basis, and some evidence suggests that depression and cognitive impairments are inversely related. Furthermore, in schizophrenia, mood symptoms seem to affect everyday functioning in a way that is unassociated with the severity of deficits in cognition and functional capacity. In contrast, in bipolar disorder, mood symptoms seem to affect real-world functioning through an adverse effect on the ability to perform critical functional skills. In both mood disorders and schizophrenia, depression appears to impact the motivation to perform potentially reinforcing acts, possibly through the induction of anhedonia. Clearly, depression has a major adverse impact on everyday functioning in all variants of severe mental illness, and improving its recognition (in the case of schizophrenia) and management has the potential to reduce the adverse impact of severe mental illness on everyday functioning. Reducing disability has the potential to have positive impacts in multiple objective and subjective aspects of functioning in severe mental illness.     

Self-reported inhibition predicts history of suicide attempts in bipolar disorder and major depression

BackgroundStudies have reliably identified an association between suicide attempts and executive functions such as decision making (DM) and inhibitory control (IC) in patients with mood disorders. As such, the present study aimed to investigate the association between inhibition, DM, impulsivity and the history of suicide attempts in individuals with bipolar (BD) or major depressive disorder (MDD), identifying which assessment instruments may be most strongly associated with suicide in clinical samples.MethodsThe sample included 80 control subjects and two groups of patients with BD and MDD, matched by age and education (26 with a history of suicide attempts [MD+], and 26 with no such history [MD−]). Participants completed behavioral and self-report measures of DM and IC, which were compared between groups using ANCOVA, followed by logistic regression for patients with mood disorders only, and the presence or absence of a history of suicide as the outcome.ResultsCognitive performance did not differ between groups. The MD+ group showed significantly higher motor and attentional impulsivity on the BIS-11 than the MD− and control groups. A regression analysis containing these scores showed that motor impulsivity was the only significant predictor of a history of suicide (OR = 1.14; 95%CI 1.00–1.30).ConclusionsSelf-reported motor impulsivity was a significant predictor of suicide. These findings underscore the importance of self-report measures in neuropsychological assessment, and their contributions to the management and prognosis of patients with mood disorders. Lastly, they point to the role of impulsivity as a target for interventions and public policy on suicide prevention.     

Cognitive dysfunction in major depression and bipolar disorder: Assessment and treatment options

Cognitive dysfunction is a recognized feature of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). Cognitive impairment is associated with poor overall functional outcome and is therefore an important feature of illness to optimize for patients’ occupational and academic outcomes. While generally people with BD appear to have a greater degree of cognitive impairment than those with MDD, direct comparisons of both patient groups within a single study are lacking. There are a number of methods for the assessment of cognitive function, but few are currently used in clinical practice. Current symptoms, past course of illness, clinical features, such as the presence of psychosis and comorbid conditions, may all influence cognitive function in mood disorders. Despite the general lack of assessment of cognitive function in clinical practice, clinicians are increasingly targeting cognitive symptoms as part of comprehensive treatment strategies. Novel pharmacological agents may improve cognitive function, but most studies of standard mood stabilizers, such as lithium and the anticonvulsants, have focused on whether or not the medications impair cognition. Non‐pharmacological strategies, such as cognitive remediation and exercise, are increasingly studied in patients with mood disorders. Despite the growing interest in strategies to manage cognitive function, there is a paucity of high‐quality trials examining either pharmacological or non‐pharmacological modes of intervention.     

Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression

Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder.     

MRI of the brainstem in patients with major depression, bipolar affective disorder and normal controls

Structural imaging studies of bipolar affective disorder or major depression have shown a spectrum of abnormal findings. However, a characteristic pattern of abnormality for either disease has not yet emerged. While the majority of studies focused on brain atrophy and the volumes of supratentorial cerebral structures, little attention has been paid to infratentorial structures. This MRI study focused on the pontomesencephalic area including the region of the raphe nuclei. The raphe nuclei are of special interest in affective disorders as they are the origin of the major serotonergic projections in this region. MRI scans of 10 bipolar I patients, 10 patients with major depression and 10 age-matched healthy control subjects were studied. The brain stem and the fourth ventricle areas as well as T2-relaxation times in the area of the raphe nuclei were evaluated. A difference between patients with major depression and control subjects for T(2)-relaxation times was found in a region of interest located along the midline of the pons. No difference was found between patients with bipolar disorder and control subjects. This finding needs to be replicated in a larger sample with more elaborated MRI techniques (multi-echo sequences) for the determination of T2-relaxation times.     

Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder

INTRODUCTION: FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls. METHODS: FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance. RESULTS: The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4. CONCLUSIONS: We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids.     

Bipolar disorder not otherwise specified: comparison with bipolar disorder I/II and major depression

OBJECTIVE: To compare the personality, clinical and comorbidity characteristics of subjects meeting diagnostic criteria for bipolar disorder not otherwise specified (BDNOS) to those with major depression and bipolar I or II disorder. METHODS: A family-based study was undertaken on the molecular genetics of depression and personality, in which the proband had been treated for depression, regardless of history, of hypomania or mania. RESULTS: The 25 subjects with BDNOS were different to the 297 subjects with major depression and similar to 75 subjects with bipolar I or II disorder on social phobia, obsessive-compulsive disorder and substance dependence comorbidity. The BDNOS subjects also had personality traits more akin to the bipolar I or II disorder subjects, especially borderline personality traits and self transcendence. CONCLUSIONS: Subjects with BDNOS, based on a history of 1-3 day recurrent hypomanias, should be included within a broader bipolar spectrum.