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Background: The familial nature of early-onset major depressive disorder (MDD) has been documented in numerous family studies of adults and is supported by studies of offspring of parents with MDD, for whom the risk is more than 3-fold. None of the published high-risk studies have gone beyond 2 generations, and few have a longitudinal design. We report results of an approximately 20-year follow-up of families at high and low risk for depression. The first 2 generations were interviewed 4 times during this period. The offspring from the second generation are now adults and have children of their own, the third generation of the original cohort., Objective: To examine the familial aggregation of psychiatric disorders and functioning in grandchildren by their parents' and grandparents' depression status., Design: Longitudinal, retrospective cohort, family study., Participants: One hundred sixty-one grandchildren and their parents and grandparents., Main Outcome Measures: Lifetime rate of psychiatric disorder and functioning in grandchildren, stratified by parental and by grandparental depression status, collected by clinicians blind to diagnoses of previous generations and to previous interviews., Results: There were high rates of psychiatric disorders, particularly anxiety disorders, in the grandchildren with 2 generations of major depression, with 59.2% of these grandchildren (mean age, 12 years) already having a psychiatric disorder. The effect of parental depression on grandchildren's outcomes differed significantly with grandparental depression status. Among families with a depressed grandparent, increased risk of anxiety (relative risk, 5.17; 95% confidence interval, 1.4-18.7; P = .01) and increased risk of any disorder (relative risk, 5.52; 95% confidence interval, 2.0-15.4; P = .002) were observed in grandchildren with a depressed parent as compared with those with nondepressed parents. The severity of parental depression, as measured by impairment, significantly increased the rate of a mood disorder in these grandchildren (relative risk, 2.44; 95% confidence interval, 1.1-5.5; P = .03). In contrast, among grandchildren with nonfamilial depression, ie, depressed parents with no depressed grandparents, there was no significant effect of parental MDD on grandchildren diagnoses. However, parental MDD, regardless of whether families had a depressed grandparent, had a significant impact on the grandchildren's overall functioning. Potential confounding variables did not affect the strength of the association with parental and grandparental depression., Conclusions: The association between parental MDD and child diagnosis is moderated by grandparental MDD status. The rates of psychopathology are highest in grandchildren of parents and grandparents with a moderately to severely impairing depression. Anxiety disorders are the early sign of psychopathology in the young grandchildren. Early interventions in the offspring of 2 generations affected with moderately to severely impairing MDD seem warranted. This familial group may be the target for neuroimaging, genetic, and other biological studies.

Background: Recent reports suggest the value of electroencephalographic and dichotic listening measures as predictors of response to antidepressants. This study examines the potential of electroencephalographic alpha asymmetry and dichotic measures of perceptual asymmetry as predictors of clinical response to 12 weeks of treatment with fluoxetine (Prozac)., Methods: Resting electroencephalography (eyes open and eyes closed) and dichotic listening with word or complex tone stimuli were assessed in depressed outpatients during a pretreatment period., Results: Fluoxetine responders (n = 34) differed from nonresponders (n = 19) in favoring left over right hemisphere processing of dichotic stimuli. They also differed in their resting electroencephalographic alpha asymmetry, particularly in the eyes open condition. Nonresponders showed an alpha asymmetry indicative of overall greater activation of the right hemisphere than the left, whereas responders did not. The relationship between hemispheric asymmetry and treatment response interacted with gender, being evident among depressed women but not men., Conclusions: The results are consistent with the hypothesis that a characteristic tendency toward greater left than right hemisphere activation is associated with favorable response to fluoxetine, whereas the opposite hemispheric asymmetry predicts poor response.

Depression may involve dysfunction of right parietotemporal cortex, a region activated during perception of affective stimuli. To further test this hypothesis, event-related brain potentials (ERPs) were measured in a paradigm previously shown to produce ERP asymmetries to affective stimuli over parietal sites in healthy adults. Pictures of patients with dermatological diseases showing disordered or healed facial areas before (negative) or after (neutral) surgical treatment were briefly exposed for 250 ms to either the left or right hemifield. ERPs of 30 unmedicated, unipolar depressed patients and 16 healthy adults, all right-handed, were recorded from 30 electrodes. A principal components analysis extracted factors which closely corresponded to distinctive ERP components previously reported for this task (N1, N2, early P3, late P3, slow wave). Significant effects of emotional content, i.e. enhanced amplitudes to negative than neutral stimuli, were found for early and late P3. Control subjects showed significant hemispheric asymmetries of emotional processing for late P3 (peak latency 460 ms), with the largest emotional content effects over the right parietal region. In striking contrast to control subjects, depressed patients did not show an increase in late P3 for negative compared to neutral stimuli over either hemisphere and had smaller late P3 amplitude than control subjects. Patients did, however, show larger early P3 (peak latency 330 ms) to negative than neutral stimuli. Results suggest intact early discrimination but abnormal late appraisal of affective content in depression, which may arise from selective inhibition of right parietal regions integral for perceiving and evaluating emotional stimuli.

Predictions that anxious and nonanxious depression would differ in perceptual asymmetry (PA), as well as in sensitivity for perceiving emotional words, were evaluated using dichotic listening tasks. A total of 149 patients having a major depressive disorder (51 with and 98 without an anxiety disorder) and 57 healthy controls were tested on fused-word and complex tone tasks. The anxious and nonanxious depression groups showed a consistent difference in PA across tasks; that is, the anxious group had a larger left-ear advantage for tones and a smaller right-ear advantage for words when compared with the nonanxious group. There was no group difference in sensitivity for perceiving emotional words. Patients having an anxious depression appear to have a greater propensity to activate right than left-hemisphere regions during auditory tasks, whereas those having a nonanxious depression have the opposite hemispheric asymmetry.

Event-related potentials to binaural complex tones were recorded from 40 depressed outpatients and 22 normal control participants at 30 electrode sites. Patients did not differ from control participants in N1 or P3 amplitude but showed greater N2. N2 was greater over right than over the left hemisphere at lateral sites in patients and control participants. A P3 asymmetry was found for control participants and patients with low scores on a physical anhedonia scale, but not for patients with high anhedonia scores. Topographic (local Laplacian) maps corresponding to P3 showed greater radial current flow over right than over left central regions in control participants. Patients with high anhedonia did not show this asymmetry, whereas patients with low anhedonia showed an intermediate asymmetry. These findings support the hypothesis that anhedonic depression is associated with dysfunction of right hemisphere mechanisms mediating the processing of complex pitch information.

Studies of brain activity in affective disorders need to distinguish between effects of depression and anxiety because of the substantial comorbidity of these disorders. Based on a model of asymmetric hemispheric activity in depression and anxiety, it was predicted that anxious and nonanxious depressed patients would differ on electroencephalographic (EEG) measures of parietotemporal activity. Resting EEG (eyes closed and eyes open) was recorded from 44 unmedicated outpatients having a unipolar major depressive disorder (19 with and 25 without an anxiety disorder), and 26 normal controls using 30 scalp electrodes (13 homologous pairs over the two hemispheres and four midline sites). As predicted, depressed patients with an anxiety disorder differed from those without an anxiety disorder in alpha asymmetry. Nonanxious depressed patients showed an alpha asymmetry indicative of less activation over right than left posterior sites, whereas anxious depressed patients showed evidence of greater activation over right than left anterior and posterior sites. The findings are discussed in terms of a model in which specific symptom features of depression and anxiety are related to different patterns of regional brain activity.

Abnormal electroencephalographic (EEG) activity has been associated with various psychiatric disorders and behaviors, including depression, suicide, and aggression. We examined quantitative resting EEG in Hispanic female adolescent suicide attempters and matched normal controls. Computerized EEG measures were recorded at 11 scalp sites during eyes open and eyes closed periods from 16 suicide attempters and 22 normal controls. Suicide attempters differed from normal controls in alpha asymmetry. Normal adolescents had greater alpha (less activation) over right than left hemisphere, whereas suicidal adolescents had a nonsignificant asymmetry in the opposite direction. Nondepressed attempters were distinguished from depressed attempters in that they accounted for the preponderance of abnormal asymmetry, particularly in posterior regions. Alpha asymmetry over posterior regions was related to ratings of suicidal intent, but not depression severity. The alpha asymmetry in suicidal adolescents resembled that seen for depressed adults in its abnormal direction, but not in its regional distribution. Findings for suicidal adolescents are discussed in terms of a hypothesis of reduced left posterior activation, which is not related to depression but to suicidal or aggressive behavior.

Despite the wide variance in therapeutic response to antidepressants, there are few clinical or biological predictors of treatment outcome. Studies have suggested the possible value of dichotic listening measures of perceptual asymmetry (PA) as predictors of treatment response. This study examined the relation between outcome of fluoxetine treatment and performance on verbal and nonverbal dichotic tests. As part of a multisite study, 86 outpatients with major depression were tested on dichotic fused-words and complex-tones tests both before and during treatment. Fluoxetine responders differed from nonresponders in having greater right-ear (left-hemisphere) advantage for dichotic words and less left-ear (right-hemisphere) advantage for complex tones. There was no change in PA during fluoxetine treatment, which indicates that PA differences between treatment responders and nonresponders are stable (trait) characteristics. An aggregate, characteristic PA measure was the best predictor of responder status in a logistic regression analysis. Findings from two clinical centers support the hypothesis that a characteristic tendency for relatively greater left-than right-hemispheric activation during dichotic listening is associated with better outcome of fluoxetine treatment.

To assess patterns of hearing loss and asymmetry in major depressive disorder (MDD), pure-tone and brief-click audiometric thresholds were measured in 59 inpatients with MDD and 40 normal control subjects. For both tasks, patients had higher bilateral thresholds, with marked hearing loss for the highest pure-tone frequency. At lower frequencies, patients displayed significant asymmetry, with poorer hearing in the left ear. After ECT, patients maintained the bilateral hearing losses; however, the baseline asymmetry resolved. These findings suggest that bilateral hearing loss may be a stable characteristic in severe depression. Poorer left ear pure-tone hearing may be present during the depressed state. The baseline asymmetry in audiometric deficits suggests right-hemisphere dysfunction in severe MDD.

Brain event-related potentials (ERPs) to probe tones in a dichotic complex tone test were recorded from right-handed depressed patients (n = 44) and normal subjects (n = 19) at homologous sites over left and right hemispheres (F3, F4; C3, C4; P3, P4; O1, O2). There were no differences between groups N1 or P2 amplitude, but patients had smaller P3 amplitude than did normal subjects. Depressed patients failed to show either the left ear advantage or behavior-related hemispheric asymmetry of P3 seen for normal subjects. Depressed patients also showed less difference in hemispheric asymmetry between same and different judgments. These findings indicate that the abnormal behavioral asymmetry for dichotic pitch discrimination in depressed patients reflects a reduction in hemispheric asymmetry and is related to relatively late stages of cognitive processing.

Cerebral laterality in bipolar and unipolar major depression was compared using visual half-field and dichotic listening measures of perceptual asymmetry. The results replicate our prior finding of abnormal laterality in bipolar depressed patients on a visuospatial test. Bipolar patients (n = 11) failed to show the left visual field (right hemisphere) advantage for dot enumeration seen for both unipolar patients (n = 43) and normal controls (n = 24). Bipolar patients performed significantly poorer than unipolar patients on normal controls for left visual field, but not right visual field stimuli. An electrophysiological correlate of abnormal visual field asymmetry in bipolar depression was found in brain event-related potentials recorded during audiospatial and temporal discrimination tasks. Bipolar patients had smaller N100 amplitudes for test stimuli in the left than right hemifield, whereas unipolar patients and normals did not. The origins of left hemifield deficits in bipolar depression are discussed in terms of right-sided dysfunction of an arousal/attentional system involving temporoparietal and possibly frontal regions.

P3 latency, a brain event-related potential (ERP) correlate of stimulus evaluation time, was measured in 25 unmedicated depressed patients and 27 normal controls during auditory temporal and spatial discrimination tasks. Patients were divided into two subgroups, one having a typical major depression (melancholia or simple mood reactive depression) and one having an atypical depression. Typical depressives had abnormally long P3 latency for the spatial task but not the temporal task. They also showed an abnormal lateral asymmetry, with longer P3 latency for stimuli in the right hemifield than the left. In contrast, atypical depressives did not differ from normals in either respect. Longer P3 latency correlated with ratings of insomnia, while abnormal lateral asymmetry correlated with reduced right visual field advantage for syllables. The P3 latency findings point to a task-related slowing of perceptual decisions in a subgroup of depression.

The relationship of cerebral laterality to outcome of treatment with antidepressants was examined by comparing perceptual asymmetry in subgroups of depressed patients formed on the basis of clinical response to a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI). Perceptual asymmetries of 63 unmedicated depressed patients were assessed for verbal and nonverbal tasks, using dichotic listening and visual half-field methods, and retests were obtained on 49 patients after about 6 weeks of treatment. There were significant differences between TCA responders and TCA nonresponders in dichotic listening and visual field asymmetries. Differences in perceptual asymmetry were specific to TCAs, in that no comparable differences existed between MAOI responders and MAOI nonresponders. Although perceptual accuracy improved following successful TCA treatment, abnormal perceptual asymmetries in TCA responders were present before and after treatment and may thereby represent state-independent characteristics.

Unmedicated endogenous (ED) and nonendogenous depressed (ND) patients were tested in the morning and evening on a dichotic click detection task and a dichotic consonant-vowel (CV) discrimination task. The ED and ND groups showed a morning to evening shift in lateral asymmetry for detecting dichotic clicks, which was opposite in direction to that previously seen for normal subjects. In contrast, there was no morning to evening shift in asymmetry for dichotic CV discrimination. Lateral asymmetry for dichotic click detection was significantly correlated with EEG sleep characteristics (sleep latency, REM period latency, REM time) and ratings of diurnal variation on the Hamilton Depression Scale. A reversal of the normal lateral asymmetry in the morning was associated with lengthened sleep latencies and with clinical ratings of diurnal variation.

The intensity needed to detect dichotic click stimuli was measured in 14 bipolar depressed patients, 19 unipolar depressed patients, and 15 normal controls. The results replicated, in unmedicated bipolar depressed patients, an earlier finding of reversed lateral asymmetry in medicated affective psychotic patients. Two new findings concern the relation of lateral asymmetry patterns to diagnostic subtypes of the Research Diagnostic Criteria and symptom ratings on the Schedule for Affective Disorders and Schizophrenia. First, patients with bipolar disorders (history of mania or hypomania) were more likely than patients with unipolar disorders to display reversed lateral asymmetry. Second, greater severity of depressive or endogenous symptoms was associated with less lateral asymmetry.

Examined the influence of diagnostic subtype of depression on perceptual asymmetry for dichotic listening and visual tachistoscopic tasks. A total of 65 unmedicated patients with major depressive disorders and 30 normal controls were tested on a verbal and nonverbal task in each modality. Patients diagnosed according to the DSM-III with melancholia had abnormal perceptual asymmetry for dichotic nonsense syllable and complex tone tasks. In contrast, patients having a nonmelancholic "atypical depression" (reactivity of mood with preserved pleasure capacity and associated features) did not differ from normal controls on these tasks, but had an increased incidence of left handedness. Bipolar depression (history of hypomania) differed from unipolar depression in showing abnormal perceptual asymmetry for a tachistoscopic dot enumeration task. Alterations of perceptual asymmetry in melancholia and bipolar depression were consistent with hypothesized right hemisphere dysfunction.