Hippocampal volume and antidepressant response in geriatric depression

BACKGROUND: Biological markers of treatment response may include structural brain changes seen on neuroimaging. While most imaging studies have focused on cerebrovascular disease, evidence is growing that the hippocampus may play a role in depression, particularly geriatric depression. METHOD: We studied 60 depressed elderly patients enrolled in a longitudinal study who were treated with antidepressant medications using a treatment guideline-based approach. Baseline and 12-week Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained via interview with a geriatric psychiatrist. All subjects had a baseline magnetic resonance imaging (MRI) brain scan. MRI scans were processed using standard protocols to determine total cerebral volume and right and left hippocampal volumes. Hippocampal volumes were standardized for total cerebral volume. MADRS scores less than 10 were used to define remission. RESULTS: When the group with the lowest quartile of standardized hippocampal volumes was compared to those above the first quartile, those with small right and total hippocampal volumes were less likely to achieve remission. In a subsequent logistic regression model controlling for age small standardized right hippocampal volumes remained significantly associated with remission. CONCLUSION: Further studies with larger sample are needed to determine if left-right hippocampal volume differences do exist in depression, and basic neuroscience studies will need to elucidate the role of the hippocampus in geriatric depression.     

Apolipoprotein E genotype and subcortical vascular lesions in older depressed patients and control subjects.

BACKGROUND: Several studies have linked geriatric depression with cerebrovascular disease. The apolipoprotein E gene (APOE) epsilon 4 allele has been associated with a variety of late-life neuropsychiatric disorders, including Alzheimer's disease, vascular dementia, and depression. METHODS: The sample consisted of 145 elderly depressive individuals and 100 nondepressed elderly control subjects. After a standardized clinical assessment, all subjects underwent a magnetic resonance imaging brain scan. Volumes of subcortical white and gray matter lesions were determined using a semi-automated method. Apolipoprotein E genotype was determined on blood sample using a standard protocol. A series of linear regression models were developed to assess the relationships between APOE genotype and white and gray matter lesion volumes. RESULTS: Older age, lower Mini-Mental State Examination score, and having any APOE epsilon 4 allele were each correlated with gray-matter lesion volume in depressed patients. Apolipoprotein E genotype was not associated with any lesion volume among control subjects. In a subsequent linear regression model, gray matter lesion volume was associated with older age, having at least one APOE epsilon 4 allele, and white matter lesion volume among depressed patients. CONCLUSIONS: These results are consistent with previous reports linking cerebrovascular disease and APOE genotype. Further studies are needed to replicate this finding in elderly depressive individuals and to explain the relationship between the APOE locus and development of central nervous system vascular pathology.     

老年与非老年抑郁症的临床特征差异

目的:探讨老年期抑郁症的临床特征。方法:以60例老年期抑郁症患者作老年组,选60例非老年期抑郁症患者为非老年组。对两组分别用汉密尔顿抑郁量表和汉密尔顿焦虑量表进行评定。结果:老年组抑郁症状中激越和疑病症状显著高于非老年组(P<0.01),老年组的躯体症状中自主神经系统症状、心血管系统症状和消化系统症状显著高于非老年组(P<0.05或P<0.01);躯体性焦虑和认知障碍、焦虑/躯体化和睡眠障碍的严重程度均显著高于非老年组(P<0.05或P<0.01)。结论:老年期抑郁症激越、疑病、躯体症状、焦虑、睡眠障碍及认知障碍等更加突出。     

Executive dysfunction and the course of geriatric depression.

BACKGROUND: Executive dysfunction is common in geriatric depression and persists after improvement of depressive symptoms. This study examined the relationship of executive impairment to the course of depressive symptoms among elderly patients with major depression. METHODS: A total of 112 nondemented elderly patients with major depression participated in an 8-week citalopram trial at a target daily dose of 40 mg. Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the Stroop Color-Word test. Medical burden was rated with the Cumulative Illness Rating Scale. RESULTS: Both abnormal initiation/perseveration and abnormal Stroop Color-Word scores were associated with an unfavorable response of geriatric depression to citalopram. In particular, initiation/perseveration scores below the median (< or =35) and Stroop scores at the lowest quartile (< or =22) predicted limited change in depressive symptoms. Impairment in other Dementia Rating Scale cognitive domains did not significantly influence the outcome of depression. CONCLUSIONS: Executive dysfunction increases the risk for poor response of geriatric depression to citalopram. Because executive functions require frontostriatal-limbic integrity, this observation provides the rationale for investigation of the role of specific frontostriatal-limbic pathways in perpetuating geriatric depression. Depressed elderly patients with executive dysfunction require vigilant clinical attention because they might be at risk to fail treatment with a selective serotonin reuptake inhibiting antidepressant.     

Dementia and depression in italian geriatric institutions

A random sample of 368 elderly residents in nine geriatric institutions in Milan was selected, and interviewed using the Intervista Psicogeriatrica, the modified Italian version of the OBS scale (82.1 % successfully completed) and the Depression scale (75.5 % successfully completed) of the Comprehensive Assessment and Referral Evaluation (CARE). The estimated prevalence rates of dementia and depression were 36 % and 30 % respectively, and 50 % for either or both diagnoses. Correlates of dementia were characteristics of the institutions (size, ownership, and admission criteria), age (for women), age at admission, female sex, and poor education. Correlates of depression were disability, length of stay in men (negative association), and marital status. Correlates of dementia and depression were also examined using multivariate analysis. The only significant independent effects on dementia were admission criteria of the institutions and age, while on depression were sex and marital status.     

APOE2 allele increased in tardive dyskinesia.

Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects.     

The APOE polymorphism and 1-year outcome in ischemic stroke: genotype-gender interaction

OBJECTIVE: In human genetic studies an effect of the apolipoprotein E gene (APOE) polymorphism on the risk, course and prognosis in chronic and acute nervous system disorders was established. We aimed to evaluate whether the APOE genotype is related to acute neurological impairments due to ischemic stroke (IS), and to outcomes (up to 1 year) indicated by severe functional disability, dependence in daily living or death. MATERIALS AND METHODS: A total of 657 patients (326 men, 331 women), divided into the three groups: E2 (APOEepsilon2/epsilon3 subjects), E3 (APOEepsilon3/epsilon3 subjects), and E4 (APOEepsilon3/epsilon4 and epsilon4/epsilon4 subjects), were analyzed. RESULTS: There was no association between the APOE genotype and baseline clinical characteristics, severity of neurological impairments during acute stroke, and 1-year outcome, when analyzing whole patient population. APOE gene interacted with gender in predicting severity of acute neurological deficit and post-stroke mortality within the period up to 1 year after the IS. Gender-stratified analysis indicated the E4 genotype as a significant independent positive predictor of death within 1 year after stroke incidence in men patients. CONCLUSION: Ischemic stroke severity and outcome may be affected by complex interactions between gender and genetic factors that warrant further exploration.     

Association between APOE polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis.

To evaluate the hypothetical link between apolipoprotein E (APOE) polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and whether presence of APOE epsilon4 allele shortens the latent period between febrile seizures and epilepsy. A further interest is whether presence of APOE epsilon4 allele has an impact on severity of the disease. Forty-seven patients with MTLE-HS were compared with 62 controls. APOE polymorphisms were determined from lymphocytes by standard methods. Eight patients (17%) and 10 controls (16.1%) were demonstrated to have one APOE epsilon4 allele. There was not any statistically significant difference in APOE epsilon4 frequency between patients and controls (P > 0.05). There was not any difference statistically according to onset age of epilepsy and the presence of APOE epsilon4 allele within patient group. APOE epsilon4 polymorphisms did not influence the severity of epilepsy. APOE epsilon4 polymorphisms had no impact on outcome after surgery. Patients with bilateral memory deficits, bilateral hippocampal atrophy and with bilateral epileptiform interictal EEG transients, were independently compared with patients having unilateral features and there were not any statistically significant differences. This study has found no association between APOE epsilon4 polymorphisms and presentation of MTLE-HS in a group of Turkish patients.     

Subcortical lesion severity and orbitofrontal cortex volume in geriatric depression.

Previous studies have shown a reduction of orbital frontal cortex volume and an increase in magnetic resonance imaging signal hyperintensities in geriatric depression. We aimed to assess the relationship between subcortical gray- and deep white-matter lesions and orbital frontal cortex volume in elderly depressives and controls.The study included 41 elderly depressed patients and 41 age-matched control subjects. The orbital frontal cortex volume was measured in both hemispheres using a standardized MRI procedure. Signal hyperintensities were rated on (T2)-weighted MRI with qualitative lesion analyses performed according to an established hyperintensity classification system.After controlling for total cerebral hemisphere, age and sex, the geriatric depressed subjects had significant reduction in orbital frontal cortex volume and compared with the control group. Multiple linear regression modeling indicated that reduced orbital frontal cortex volumes were significantly associated with increased subcortical gray-matter lesions.Our study confirmed the reduction of OFC volume in geriatric depressed subjects. We also suggest that subcortical lesions may decrease OFC volume. Further studies are needed to understand how subcortical lesions may be related to OFC volume changes.     

Transient heterosynaptic depression in the hippocampal slice

Two independent, excitatory, monosynaptic afferent fiber systems projecting onto basal and apical dendritic layers of the CA1 sub-field of the hippocampus were tested for interactive effects. Long-term potentiation of either of the pathways was accompanied by a transient depression in the other pathway. Similar transient depression could be elicited by antidromic stimulation of the CA1 cells. No long-term heterosynaptic effects were observed.     

A three-factor analytic model of the MADRS in geriatric depression

OBJECTIVE: Major depression is a heterogeneous disorder, perhaps comprising several clinical subtypes or subgroups of symptoms. This study examined whether items on the Montgomery-Asberg Depression Rating Scale (MADRS) form distinct symptom subgroups among geriatric depressive patients that might form the basis of new outcome measures for tracking treatment effects. METHOD: The study examined a sample of 225 adults age 59 and older diagnosed with major depression. Factor analysis with oblique rotation was used to analyze baseline MADRS item scores. RESULTS: Three distinct interpretable factors were obtained; all ten items loaded <0.60 on a domain. The first factor, dysphoric apathy/retardation, comprised five items: apparent sadness, reported sadness, lassitude, reduced concentration, and inability to feel. Psychic anxiety, the second factor, included three items: inner tension, pessimistic thoughts, and suicidal thoughts. The third factor, vegetative symptoms, resulted from items involving sleep and appetite. CONCLUSIONS: The study produced three interpretable MADRS factors reflecting geriatric depression dimensions that may be useable to monitor focused treatment outcomes.     

Apolipoprotein E (APOE) phenotype and APOE concentrations in multiple sclerosis and acute herpes zoster

Objectives – There are three major isoforms of apolipoprotein E (apoE), namely apoE2, apoE3, and apoE4, that are products of three alleles (ε₂,ε₃,ε₄) at a single gene locus on chromosome 19. It is well known that the presence of apoE4 increases the risk for the development of Alzheimer's disease and atherosclerosis. The aim of the study was to examine if apoE polymorphism or apoE levels contribute to the severity of the disease in patients with multiple sclerosis or the outcome of nerve damage in patients with herpes zoster infection. Material and methods – We examined apoE phenotype of 105 MS patients and 41 patients with herpes zoster. We also measured serum and cerebrospinal fluid (CSF) levels of apoE from 93 patients with definite MS using enzyme linked immunosorbent assay. Results – There were no differences in apoE allele frequencies in MS or herpes zoster patients compared to the allele frequencies of controls. The levels of serum or CSF apoE did not differ from those of age‐matched controls, nor did they correlate with the disease activity. Conclusion – We conclude that apoE does not contribute to the activity of MS or the outcome of herpes zoster.     

卒中后抑郁与脑卒中患者载脂蛋白E水平对照研究

目的:探讨卒中后抑郁(PSD)患者载脂蛋白E(ApoE)水平特点,为PSD的诊断提供新的客观依据。方法:采用实时荧光定量PCR技术和酶联免疫吸附法(ELISA)检测PSD患者及卒中后非抑郁患者ApoE水平。结果:PSD组ApoE基因mRNA表达量低于卒中组,差异具有统计学意义(P<0.01);PSD组血清ApoE水平高于卒中组,差异具有统计学意义(P<0.05)。结论:PSD患者外周血ApoE基因mRNA表达和血清ApoE水平与卒中非抑郁患者不同。     

Effect of apolipoprotein E genotype on in-hospital mortality following intracerebral haemorrhage

OBJECTIVE: To determine the relationship between the apolipoprotein E (APOE) epsilon4 allele and in-hospital mortality from intracerebral haemorrhage (ICH). MATERIAL AND METHODS: Patients admitted to two acute stroke units with ICH were prospectively evaluated and APOE genotyped. In-hospital survival was recorded in 176 patients. RESULTS: There were 85 men and 91 women, mean age 68 years. Fifty-two (30%) of the 176 patients died in hospital. After adjusting for sex, age, hospital, and race, increased age (P = 0.009) and the presence of the APOEepsilon4 allele (P = 0.026) significantly reduced in-hospital survival. CONCLUSION: The APOEepsilon4 allele in this population may be associated with poor survival following ICH.     

Chronic pain and depression among geriatric psychiatry inpatients

OBJECTIVES: We examined whether chronic pain among depressed geriatric inpatients was associated with several clinical variables-comorbid psychiatric and medical diagnoses, length of hospitalization, suicidal ideation, and sleep duration. METHODS: Medical charts of inpatients admitted to a geriatric psychiatry unit over 2 years were examined retrospectively; 148 patients with a depressive disorder were identified. Admission pain assessments were used to classify whether patients had chronic pain. Other variables of interest were collected from charts. RESULTS: 62% of patients reported chronic pain. In multivariate regression analysis, depressed older adults with chronic pain were more likely to report suicidal ideation, be diagnosed with personality disorder, have higher medical burden, and experience decreased total sleep time compared to depressed older adults without chronic pain. CONCLUSIONS: Chronic pain--common in depressed older adults--may influence clinical features of depression and should be assessed as a possible suicide risk factor. Prospective studies should examine causal relationships and determine the effects of adequate pain treatment on depression course and suicide risk in older adults.     

Hippocampal volume in geriatric depression.

BACKGROUND: There is a growing literature on the importance of hippocampal volume in geriatric depression. METHODS: We examined hippocampal volume in a group of elderly depressed patients and a group of elderly control subjects (N = 66 geriatric depressed patients and 18 elderly nondepressed control subjects) recruited through Duke's Mental Health Clinical Research Center for the Study of Depression in the Elderly. The subjects received a standardized evaluation, including a magnetic resonance imaging scan of the brain. Patients had unipolar major depression and were free of comorbid major psychiatric illness and neurologic illness. Differences were assessed using t tests and linear regression modeling. RESULTS: Accounting for the effects of age, gender, and total brain volume, depressed patients tended to have smaller right hippocampal volume (p =.014) and left hippocampal volume (p =.073). Among depressed patients, age of onset was negatively but not significantly related to right hippocampal volume (p =.052) and to left hippocampal volume (p =.062). We noted that among subjects with either right or left hippocampal volume of 3 mL or less, the vast majority were patients rather than control subjects. CONCLUSIONS: These results support a role for hippocampal dysfunction in depression, particularly in late-age onset depression. Longitudinal studies examining both depressive and cognitive outcomes are needed to clarify the relationships between the hippocampus, depression, and dementia.     

Temporal lobe epilepsy, depression, and hippocampal volume

Objective:   To evaluate the relationship between hippocampal volume loss, depression, and epilepsy.
Background:   There is a significantly increased incidence of depression and suicide in patients with epilepsy. Both epilepsy and depression are associated with reduced hippocampal volumes, but it is uncertain whether patients with both conditions have greater atrophy than those with epilepsy alone. Previous studies used depression measures strongly weighted to current state, and did not necessarily assess the influence of chronic major depressive disorder (trait), which could have a greater impact on hippocampal volume.
Methods:   Fifty-five epilepsy patients with complex partial seizures (CPS) confirmed by electroencephalography (EEG) had three-dimensional (3D)-spoiled gradient recall (SPGR) acquisition magnetic resonance imaging (MRI) scans for hippocampal volumetric analysis. Depression screening was performed with the Beck Depression Inventory (BDI, 51 patients) and with the structured clinical inventory for DSM-IV (SCID, 34 patients). For the BDI, a score above 10 was considered mild to moderate, above 20 moderate to severe, and above 30 severe depression. MRI and clinical analysis were performed blinded to other data. Statistical analysis was performed with Systat using Student's t test and analysis of variance (ANOVA).
Results:   There was a significant interaction between depression detected on SCID, side of focus, and left hippocampal volume. Patients with a diagnosis of depression and a right temporal seizure focus had significantly lower left hippocampal volume. A similar trend for an effect of depression on right hippocampal volume in patients with a right temporal focus did not reach statistical significance.
Conclusions:   Our results suggest that patients with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone.