Biomedical subjects

Andrew F Leuchter

Publications and source records attributed to Andrew F Leuchter.

At least 19 recordsLinked to original sources

PubMed2006

Neurophysiologic changes during estrogen augmentation in perimenopausal depression.

BACKGROUND: Estrogen augmentation of antidepressant medication has been an effective treatment in a subgroup of women experiencing affective symptoms during perimenopause. It has been suggested that estrogen facilitates serotonergic transmission in brain regions involved in mood disorders. We investigated differences in physiologic brain changes with estrogen augmentation in women with perimenopausal depression who reached remission compared to those who did not reach remission. We also assessed whether such changes were correlated with serum hormone levels. METHODS: Quantitative electroencephalography (QEEG) was used to examine neurophysiologic brain changes in remission and non-remission of depressive symptoms. Women with major depressive disorder (MDD) in partial remission who were taking antidepressant medication for a minimum of 8 weeks and were experiencing two or more perimenopausal symptoms (hot flashes, night sweats, irregular periods, memory impairment, vaginal dryness) were recruited from the community. Absolute power, relative power, and QEEG cordance, a measure that has moderately strong associations with cerebral perfusion, were obtained before and after 6 weeks of treatment with 0.625 mg of conjugated estrogen per day. RESULTS: Women who experienced remission of depressive symptoms (Ham-D< or =7) had a significant decrease in right frontal QEEG cordance (p=0.008, t((8))=-3.54) which was not present in non-remitters. No significant correlations were found between hormone levels and QEEG cordance. CONCLUSION: In women with perimenopausal depression, physiologic brain changes in the right frontal region during estrogen augmentation were associated with remission of depression.

Administration, Oral↗

PubMed2006

Does the clinical course of depression determine improvement in symptoms and quality of life?

Clinical course factors characterizing individuals' history with depression may be helpful in predicting treatment-related change in quality of life (QOL). Such factors have been studied in relation to symptomatic change with mixed results. This 9-week single-blind treatment trial using reboxetine (1 week placebo lead-in) evaluated the impact of age of onset, history of antidepressant treatment, duration of index episode, number of past episodes, and the presence of precipitating stress on depressed individuals' treatment response. We found that QOL did not normalize along with clinical remission in all areas. Using multivariate analysis, we found that age of onset, history with antidepressants, and the presence of identifiable precipitating stress were all significant predictors of QOL change (controlling for symptomatic change); some factors also predicted symptomatic improvement. Our results support the trend of distinguishing between treatment-related change in QOL and symptomatic change and suggest clinical course factors as promising predictors of QOL.

Adult↗

PubMed2006

Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression.

OBJECTIVE: Decreases in prefrontal electroencephalogram (EEG) cordance that are detectable as early as 48 hours after the start of medication have been related to clinical outcome in treatment trials for major depressive disorder. The relationship between brain changes during the placebo lead-in phase and medication treatment outcome is unknown. The authors hypothesized that decreases in prefrontal cordance during the placebo lead-in phase would be associated with better clinical outcome in subjects treated with antidepressants. METHOD: Data were pooled examining 51 adults with major depressive disorder from two independent double-blind placebo-controlled trials. A 1-week single-blind placebo lead-in phase preceded 8 weeks of randomized treatment with medication (fluoxetine 20 mg or venlafaxine 150 mg) or placebo. The authors obtained quantitative EEG cordance measures at baseline and at the end of the placebo lead-in period. Relationships between regional cordance changes at the end of the placebo lead-in period and clinical outcome (the final 17-item Hamilton Rating Scale for Depression scores) were examined using multiple linear regression analysis. RESULTS: As hypothesized, decreases in prefrontal cordance during the placebo lead-in period were associated with lower final Hamilton depression scale scores in subjects randomly assigned to medication. Prefrontal changes explained 19% of the variance in final Hamilton depression scale scores. CONCLUSIONS: Neurophysiological changes during a placebo lead-in period may serve as nonpharmacodynamic biomarkers of eventual treatment outcomes in clinical trials for major depressive disorder.

Adult↗

PubMed2005

Influence of age, gender, health status, and depression on quantitative EEG.

Quantitative electroencephalography (QEEG) has shown increasing utility in assessing brain function in clinical research studies of depression. QEEG findings may be influenced by a variety of factors other than the presence of depression, including age, gender, depression severity, and physical health status. Many of these factors have not been systematically evaluated. We therefore examined QEEG measures in 104 subjects with depression and normal controls to determine the influence of these factors. We examined QEEG power as well as cordance, a QEEG measure that has a stronger association with cerebral perfusion than conventional QEEG measures. Prefrontal cordance in the theta band has been associated with the pathophysiology of depression and response to treatment. We found that prefrontal cordance and relative power in the theta band were unaffected by age, gender, severity of depression, and health status, while prefrontal absolute power was higher in women than men. All of these measures were different from global measures of absolute and relative power, which were influenced by age, gender, and health status. These findings suggest that prefrontal cordance in depressed patients is not significantly affected by factors of age, gender, severity of depression, or physical illness. Global measures of power, and to a lesser extent prefrontal absolute power, must be interpreted with regard to confounding factors of age, gender, physical illness, and severity of depression.

Adult↗

PubMed2005

Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study.

Previous studies in unipolar depression have shown that early decreases in prefrontal values of the QEEG cordance measure identified responders to pharmacotherapy. These studies have all examined individuals who were drug-free prior to the first physiologic assessment, yet in the clinical management of treatment resistant depression (TRD), many patients undergo changes in treatment without a drug-free interval between treatments. Here, we investigated whether cordance decreases were associated with response in Stage I TRD subjects without wash-out between treatment trials. Awake EEGs were recorded from 12 adults with unipolar depression. Subjects were receiving naturalistic treatment, had failed SSRI monotherapy, and were starting a new treatment prescribed by their treating psychiatrists. EEG data were recorded before starting the new treatment and after approximately 1 week. Six of the 12 subjects responded to treatment after 8--10 weeks. Five of the six responders showed an early cordance decreases, compared with two of the six nonresponders (accurate characterization in 75% of the cases). Consistent with previous treatment trials, decreases in prefrontal cordance differentiated responders from nonresponders in this setting as well. These findings suggest that cordance biomarkers may be a useful tool in effectiveness trials that parallel clinical practices in SSRI nonresponders, and may not require a wash-out period between treatments.

Adult↗

PubMed2005

Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.

Adolescent↗

PubMed2005

Characteristics of insured and noninsured outpatients with depression in STAR(*)D.

OBJECTIVE: This study examined data from the first 1,500 patients with major depressive disorder who were entered into the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) and compared baseline characteristics of outpatients on the basis of their insurance status. METHODS: We compared the demographic and clinical characteristics and the features of the presenting symptoms of outpatients with private insurance, public insurance, Medicaid and Medicare, or no insurance who were seeking treatment for depression. RESULTS: Valid insurance data were available for 1,452 patients. Compared with patients with private insurance, patients with public or no insurance were more likely to be members of a racial or ethnic minority group, unmarried, less educated, and unemployed. Patients were more likely to attend primary care clinics if they had public insurance (46 percent) compared with private insurance (34 percent) or no insurance (30 percent). Compared with the other groups, patients with public insurance had the greatest number and severity of comorbid medical conditions. In general, compared with patients with private insurance, those with public or no insurance had greater severity of depression, more comorbid psychiatric symptoms, lower life satisfaction scores, and greater functional impairment. These findings remained after the analyses adjusted for gender, employment, comorbid medical conditions, race, and duration of illness. CONCLUSIONS: Compared with patients with private insurance, those with public or no insurance had a more chronic, more severe, and more disabling form of depression.

Adult↗

PubMed2005

Estrogen augmentation of antidepressants in perimenopausal depression: a pilot study.

OBJECTIVE: To investigate the effects of estrogen augmentation on mood and memory in women with perimenopausal depression who had experienced a partial response to antidepressant medications. METHOD: In a double-blind, placebo-controlled trial, 17 subjects taking antidepressant medication were randomly assigned to either 0.625 mg/day of conjugated estrogen (N = 11) or matching placebo (N = 6) for 6 weeks. Women between the ages of 40 and 60 years with DSM-IV major depressive disorder (MDD) in partial remission who had been taking antidepressant medication for a minimum of 8 weeks and were experiencing 1 or more perimenopausal symptoms (hot flashes, night sweats, irregular periods, sleep disturbance, memory impairment) were recruited from the community. The primary outcome measures were the final scores for the Hamilton Rating Scale for Depression (HAM-D) and the Buschke Selective Reminding Test. Data were gathered from April 2002 to August 2003. RESULTS: Women receiving estrogen had a significantly larger decrease in HAM-D scores than women receiving placebo (t = 2.86, df = 15, p = .012). Group differences in tests of verbal memory were not significant, although improved scores in verbal memory were significantly correlated with a decrease in follicle-stimulating hormone (p = .021). CONCLUSION: Short-term, low-dose estrogen augmentation of antidepressant medication was significantly associated with improved mood, but not memory, in perimenopausal women with MDD in partial remission.

Adult↗

PubMed2004

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression.

RATIONALE: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials. OBJECTIVE: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD. METHODS: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24) or venlafaxine ( n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of </=10. RESULTS: Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects ( P<0.006) and medication responders in particular ( P<0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia ( P<0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders. CONCLUSIONS: These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.

Adult↗

PubMed2004

Predictors of improved mood over time in clinical trials for major depression.

The objective of this exploratory analysis was to use a repeated measures modeling approach to identify potential predictors of improved mood over time in patients with major depression. Fifty-one subjects with major depressive disorder (MDD) were enrolled in a 1-week single blind placebo lead-in, followed by an 8-week, double-blind placebo-controlled treatment with either fluoxetine or venlafaxine. Hierarchical linear regression models were used to identify baseline and placebo lead-in predictors of change in repeated measures of the Hamilton Depression Rating Scale (HDRS) during treatment. Non-specific predictors of improved mood included decreased prefrontal activity during placebo lead-in as measured by quantitative electroencephalographic cordance, lower pretreatment depressed mood on the HDRS, shorter duration of current episode, increased verbalization of suicidal thoughts, no family history of mood disorders, less severe middle insomnia, higher guilt, lower somatic anxiety, and younger age. Moderators of improved mood included somatization, paranoid ideation, and self-reported depressed mood. We also found that change in prefrontal cordance after randomization mediated the effects of middle insomnia, suicidal thoughts, and family history of mood disorders. We recommend the use of repeated measures modeling, and the exploration of relationships among biological and psychological factors, for future analyses of clinical trial data.

Adult↗

PubMed2004

Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers.

OBJECTIVE: Exposure to methamphetamine is associated with long-lasting reductions in markers for dopaminergic neurons in preclinical models and in humans. These changes may be associated with alterations in brain electrical activity and in cognition. METHODS: The sample included 9 methamphetamine-dependent subjects and 10 non-drug-using volunteers. Methamphetamine-dependent subjects were hospitalized for 4 days to document abstinence; non-drug-using volunteers were studied as outpatients. EEGs were recorded in the eyes-closed resting state, and absolute EEG power in each frequency band (0.5-4 Hz, 4-8 Hz, 8-12 Hz, and 12-20 Hz) was measured using a fast Fourier transform. EEG power was log-transformed prior to analysis. Cognition was measured using computerized reaction time tasks. RESULTS: Within the methamphetamine-dependent group only, increased theta quantitative EEG (QEEG) power correlated significantly with reaction time on tasks that were more difficult or that were degraded by fatigue. Increased theta QEEG power also correlated with reduced accuracy on a working memory task. CONCLUSIONS: Increased QEEG power in the theta band is associated with worse performance on reaction time tasks in the methamphetamine-dependent sample but not in the non-drug-using volunteers. SIGNIFICANCE: Methamphetamine dependence is associated with pathological alterations in brain electrical activity and in cognitive performance. QEEG appears to provide a sensitive measure of methamphetamine-associated alterations in brain function.

Adult↗

PubMed2004

Pretreatment neurophysiologic function and ECT response in depression.

OBJECTIVES: Recent brain imaging studies have provided evidence that brain function assessed prior to treatment of depression may be associated with eventual treatment response. The present study tested the hypothesis that brain activity in midline apical quantitative EEG (QEEG) electrodes would be associated with therapeutic response to electroconvulsive therapy (ECT). METHODS: Ten treatment-refractory patients with unipolar or bipolar depression received a Hamilton Rating Scale for Depression (Ham-D) at baseline, during, and following ECT treatment. Resting, eyes-closed, 35-lead QEEG recordings were done 1 day before the initial ECT treatment. Data were analyzed using QEEG power and cordance. RESULTS: The mean of the theta-band pretreatment cordance from the central brain region was strongly associated with percentage decrease in Ham-D score over the course of treatment (r = 0.80, P = 0.005). QEEG cordance from other brain regions and power from all brain regions did not show an association with clinical improvement. CONCLUSIONS: Depressed subjects with higher pretreatment central cordance appear to be more likely to experience therapeutic benefits of ECT. The location of central electrodes over the cingulate cortex may indicate that pretreatment cingulate activity is associated with response to ECT.

Bipolar Disorder↗

PubMed2004

Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant.

OBJECTIVE: To evaluate the association between treatment expectations and response in a 9-week, single-blind experimental antidepressant treatment study. METHOD: Twenty-five adult subjects meeting DSM-IV criteria for major depressive disorder with Hamilton Rating Scale for Depression (HAM-D) scores of >/= 17 completed a treatment trial using the experimental antidepressant reboxetine. Following a 1-week placebo lead-in, subjects received single-blind treatment for 8 weeks with reboxetine 8 to 10 mg/day. During the screening visit, subjects were asked to self-rate their expectations of the effectiveness of the study medication. Forced-choice responses were "not at all effective," "somewhat effective," or "very effective." Response to treatment was defined as a final HAM-D score of </= 10 at the end of the 9-week trial. Data were collected from October 1999 to July 2001. RESULTS: Subjects with a higher pretreatment expectation of medication effectiveness had a greater likelihood of response. Of the subjects who reported an expectation that the medication would be very effective, 90.0% (N = 9) responded to treatment, while only 33.3% (N = 5) of those who reported expecting medication to be somewhat effective responded to treatment (chi(2) = 7.819, p <.005). There was no association between the level of depression severity, duration of current episode, number of prior episodes, or basic demographic factors and treatment outcome. CONCLUSIONS: These findings indicate that individuals with high baseline expectations of improvement demonstrate a significantly higher level of response to reboxetine than those with lower expectations of improvement with treatment. The data in this study suggest that a subject's expectation of efficacy is associated with the outcome of experimental antidepressant treatment.

Adolescent↗

PubMed2003

Quantitative EEG abnormalities in recently abstinent methamphetamine dependent individuals.

OBJECTIVE: Methamphetamine exposure is associated with long-lasting reductions in markers for dopaminergic neurons in preclinical models and probably in humans. Quantitative electroencephalography (EEG) has been used to characterize abnormalities in brain function in a number of disorders, including cocaine dependence, but this technique has not been used to characterize abnormalities associated with methamphetamine dependence. METHODS: The sample included 11 methamphetamine dependent subjects and 11 non-drug using volunteers. Methamphetamine dependent subjects were hospitalized for 4 days to document abstinence; non-drug using volunteers were studied as outpatients. EEGs were recorded in the eyes-closed resting state, and absolute EEG power in each frequency band (0.5-4, 4-8, 8-12, and 12-20 Hz) was quantitated using a fast Fourier transform. EEG power was log-transformed prior to analysis. Conventional, EEG tracings were interpreted by a qualified electroencephalographer who was blinded to the subjects' identity. RESULTS: Methamphetamine dependent volunteers with 4 days of abstinence had increased EEG power in the delta and theta bands. Power in the alpha and beta bands did not differ between the groups. Within the methamphetamine dependent group, a majority of the conventional EEGs were abnormal (64%), compared to 18% in the non-methamphetamine using group. CONCLUSIONS: Recently abstinent methamphetamine dependent subjects demonstrate QEEG abnormalities that are consistent with a generalized encephalopathy. SIGNIFICANCE: Encephalopathic changes in brain electrical activity, as found here in methamphetamine dependence, are frequently associated with a range of cognitive and psychiatric abnormalities, suggesting further avenues of investigation.

Adult↗

PubMed2002

Cognitive and physiologic correlates of subclinical structural brain disease in elderly healthy control subjects.

CONTEXT: Healthy elderly persons commonly show 4 types of change in brain structure-cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities-as forms of subclinical structural brain disease (SSBD). OBJECTIVES: To characterize the volumes of SSBD present with aging and to determine the associations of SSBD, physiology, and cognitive function. DESIGN: Cross-sectional study. SETTING: University of California, Los Angeles, Neuropsychiatric Institute. SUBJECTS: Forty-three community-dwelling healthy control subjects, aged 60 through 93 years. MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging, neuropsychological testing, and quantitative electroencephalographic coherence (functional connectivity) between brain regions. RESULTS: Regression models demonstrated significant relationships between SSBD volumes, age, cognitive performance, and connectivity. Cortical and central atrophy and periventricular hyperintensities had significant associations with age while deep white-matter hyperintensities did not. Posterior atrophy showed stronger associations with age than did anterior atrophy. Only a subset of subjects at older ages showed large SSBD volumes; older subjects primarily showed increasing variance of SSBD. Although all subjects scored within the normal range on cognitive testing, SSBD volume was inversely related to performance, most notably on the Trail-Making Test part B and the Shipley-Hartford Abstract Reasoning test. Coherence had significant associations with SSBD. Path analysis supported mediation of the effects of deep white-matter hyperintensities and periventricular hyperintensities on cognition by altered connectivity. For several measures, cognitive performance was best explained by coherence, and only secondarily by SSBD. CONCLUSIONS: Modest volumes of SSBD were associated with decrements in cognitive performance within the normal range in healthy subjects. Lower coherence was associated with greater volumes of SSBD and increasing age. Path analysis models suggest that brain functional connectivity mediates some effects of SSBD on cognition.

Aged↗

PubMed2002

Estrogen replacement therapy is associated with less progression of subclinical structural brain disease in normal elderly women: a pilot study.

BACKGROUND: Cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities are reported in normal aging. OBJECTIVES: We examined the effects of estrogen replacement therapy (ERT) on these forms of 'subclinical structural brain disease' (SSBD) in normal, postmenopausal women in a pilot, naturalistic, longitudinal study of 15 subjects. METHODS: Two assessments were performed at least two years apart, with volumetric magnetic resonance imaging (MRI) and neuropsychological testing. RESULTS: Women receiving open-label ERT showed significantly less progression of SSBD than those who did not. CONCLUSIONS: The association between reduced SSBD progression and ERT suggests this intervention could help preserve normal brain structure in healthy elderly women.

Aged↗

PubMed2002

Early changes in prefrontal activity characterize clinical responders to antidepressants.

Previous studies have shown that changes in brain function precede clinical response to antidepressant medications. Here we examined quantitative EEG (QEEG) absolute and relative power and a new measure, cordance, for detecting regional changes associated with treatment response. Fifty-one adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs. placebo. Data were recorded at baseline and after 48 h and 1 week on drug or placebo. Baseline and change from baseline values were examined for specific brain regions in four subject groups (medication and placebo responders and nonresponders). No regional baseline QEEG differences were found among the groups; there also were no significant changes in theta power over time. In contrast, medication responders uniquely showed significant decreases in prefrontal cordance at 48 h and 1 week. Clinical differences did not emerge until after four weeks. Subjects with greater changes in cordance had the most complete 8-week responses. These findings implicate the prefrontal region in mediating response to antidepressant medications. Cordance may have clinical applicability as a leading indicator of individual response.

Adult↗

PubMed2002

Changes in brain function of depressed subjects during treatment with placebo.

OBJECTIVE: It has been proposed that 50%-75% of the efficacy of antidepressant medication represents the placebo effect, since many depressed patients improve when treated with either medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined. METHOD: Fifty-one subjects with major depression were enrolled in one of two independent, 9-week double-blind, placebo-controlled studies in which either fluoxetine (N=24) or venlafaxine (N=27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders. RESULTS: No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in medication nonresponders or placebo nonresponders (who showed no significant change). There was no significant change in QEEG power during treatment. CONCLUSIONS: These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.

Adult↗