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Objective: The study compared the neuropsychological functioning of patients with first-admission schizophrenia with that of patients with first-admission psychotic affective disorders. Method: Data came from the Suffolk County Mental Health Project, an epidemiological study of first-admission psychotic disorders. Subjects with a diagnosis of schizophrenia (N=102) and psychotic affective disorders, including bipolar disorder with psychotic features (N=72) and major depressive disorder with psychotic features (N=49), were compared on a battery of neuropsychological tests administered 2 years after the index admission. Results: Subjects with schizophrenia performed worse than those with the psychotic affective disorders, even after adjusting the results for differences in demographic characteristics and general intellectual functioning. The most consistent differences were on tests of attention, concentration, and mental tracking. The two psychotic affective disorder groups were indistinguishable in performance on the neuropsychological tests. Conclusions: Even early in its course, schizophrenia is distinguishable from psychotic affective disorders by global and specific neuropsychological deficits. These deficits might contribute to the disability and poor outcome associated with schizophrenia in the mid- and long-term course.

Objective: Published reports indicate that African Americans are underrepresented among patients treated with ECT. The reason for this disparity in practice has not been determined. This study addressed this question by using existing data on a large series of patients treated with ECT at a single academic medical center. Method: The hospital's administrative databases were used to select Caucasian and African American patients with a diagnosis of major affective disorder treated over the period from November 1993 to March 2002. Independent variables were age, sex, treatment unit, readmission within 30 days, type of insurance, and geographic zone of residence. The dependent variable was likelihood of being treated with ECF, computed for each race group. Results: Caucasians were more likely than African Americans to be treated with ECT (odds ratio=4.71; 95% confidence interval [Cl]=3.77-5.90). None of the variables examined provided an explanation for this disparity. When all of the variables were controlled simultaneously, the likelihood of being treated with ECT remained significantly higher for Caucasians than for African Americans (odds ratio=2.48; 95% Cl=1.89-3.25). Conclusions: The racial disparity in the use of ECT cannot be explained on the basis of the variables studied. It is not an artifact of the age of the patient population, nor can it be explained on the basis of insurance coverage, the social class of the patients, or their illnesses' being more treatment resistant. The authors propose several other hypotheses, including explanations relating to clinical presentation, differential response to other treatments, differences in patients' willingness to consent, and physicians' behavior, that could be explored by using other methods.

Objective: Psychiatric literature over the past 100 years suggests that Jews are at higher risk for affective disorders than members of other religious groups. To examine these claims, the authors analyzed data from the National Institute of Mental Health Epidemiologic Catchment Area (ECA) study. In addition, the relationships among gender, alcoholism, and major depression were investigated. Method: The period prevalence and lifetime rates of DSM-III major depression among Jews, Catholics, Protestants, individuals in other religious groups, and individuals with no religious affiliation were examined in the Los Angeles and New Haven, Conn., ECA data. Logistic regression with covariates for site, gender, marital status, and socioeconomic status was used to estimate odds ratios and 95% confidence intervals. The calculated rates, based on the combined data from ECA study waves 1 and 2 for the white population, were weighted according to the 1980 U.S. population census. Female-to-male rate ratios and rates of alcohol abuse/dependence were also obtained. Results: While no differences were found among females, Jewish males had significantly higher rates of major depression than Catholics, Protestants, and all non-Jews combined. Jews had a 1:1 female-to-male ratio for major depression, in contrast to the other religious groups, which approached the universal 2:1 ratio. Rates of alcohol abuse/dependence were inversely related to rates of major depression. Conclusions: The results support only in part the earlier reports that Jews have higher rates of major depression. The equal gender distribution of major depression among Jews may be associated with the lower rate of alcoholism among Jewish males.

Objective: This study tested the impression that there have been significant shifts in the relative diagnostic frequencies of schizophrenia and major affective disorders. Method: Data on discharge diagnoses from 1972 to 1988 were gathered from six North American psychiatric teaching hospitals (data from one extended through 1991), and rates for schizophrenia and major mood disorders were evaluated. Results: Total annual discharges increased by 6.6% during the study period. Large reciprocal shifts in the frequencies of diagnoses of schizophrenia and major affective disorders were found; schizoaffective disorder was a minor diagnosis. Beginning in the early 1970s, a gradual increase in the frequency of diagnoses of major affective disorders at all sites was accompanied by a corresponding decrease in diagnoses of schizophrenia at five of the six centers. Schizophrenia diagnoses decreased from a peak of 27% in 1976 to 9% in 1989 (a threefold decrease), and diagnoses of major affective disorders rose from a low of 10% in 1972 to 44% in 1990 (a fourfold increase). Conclusions: Several forces may have influenced these changes. 1) DSM-III narrowed the definition of schizophrenia and broadened the category of major affective disorders. 2) Treatment-oriented diagnostic bias associated with the availability of lithium and other mood-altering agents may have encouraged consideration of affective disorders. 3) Economic and social forces, including better third-party reimbursement rates, may have favored affective diagnoses. 4) True increases in the incidence of affective disorders may have occurred. 5) Although a real decrease in new cases of schizophrenia may have occurred, this effect was probably minor and dominated by a larger shift of such diagnoses to affective categories.

Objective: This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. Method: Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N=57), unipolar depression (N=29), and bipolar disorder (N=16). Results: The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test - Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. Conclusions: These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.

Objective: This analysis aimed to quantify the long-term stability of distinctions between nonbipolar, bipolar II, and bipolar I affective disorders and to determine the predictors of shifts in patients' diagnoses among these categories. Method: Probands entered the study as they sought treatment for manic, major depressive, or schizoaffective disorder diagnosed according to the Research Diagnostic Criteria. After thorough baseline evaluations, 605 patients with nonbipolar major depressive disorder or schizoaffective disorder, depressed type; 96 with bipolar II disorder; and 231 with bipolar I disorder or schizoaffective disorder, manic type, began the follow-up study. Direct interviews took place at 6-month intervals for the first 5 years and annually thereafter. Results: Only 20 (5.2%) of the 381 initially nonbipolar probands who completed 10 years of follow-up developed mania during that time, and only 19 (5.0%) developed hypomania. A slightly higher proportion of the 67 who began with bipolar II disorder developed mania during the 10 years. Although 101 (66.4%) of the 152 bipolar I or schizoaffective manic probands developed subsequent manic episodes, only 11 (7.2%) developed hypomanic episodes and no mania. Young age at intake and at onset and chronicity of the index episode predicted shifts from nonbipolar to bipolar II disorder. Psychosis and a family history of mania predicted shifts from nonbipolar to bipolar I disorder. Conclusions: The high stability of baseline distinctions between nonbipolar, bipolar II, and bipolar I disorders, in combination with previously described family study data, strongly supports the separation of these disorders for both clinical and research purposes.

Objective: This study investigated whether the distinction between schizoaffective disorder and affective disorders with mood-incongruent psychotic features as described in DSM-III-R is reflected by aggregation of schizophrenia in the families of probands with the former disorder and aggregation of affective disorders mainly among the relatives of probands with the latter type of disorders. Method: The probands were 118 inpatients with definite lifetime diagnoses of DSM-III-R schizoaffective disorder or a major mood disorder with incongruent psychotic features according to structured clinical interviews. Diagnostic information on 475 of the probands' first-degree relatives was gathered through direct interviews (with 80% of the living first-degree relatives) or the family history approach. The rates of affective and psychotic disorders among these relatives were then compared with those among the relatives of a comparison group of 109 interviewed individuals from the general population who were matched on sociodemographic factors to the inpatient probands. Results: With regard to the familial aggregation of schizophrenia, the DSM-III-R distinction emerged as valid. However, the risk of unipolar affective disorders was enhanced in the families of all of the subgroups of patients studied. The unipolar/bipolar distinction in both DSM-III-R diagnostic groups was reflected by distinct patterns of bipolar disorders in the relatives. Conclusions: The results partly support the DSM-III-R dichotomy of schizoaffective disorder and affective disorders with mood-incongruent psychotic features. Although the differences between these two diagnostic groups were significant, the magnitude of the differences remained relatively modest.

Researchers have increasing emphasized the distinction between positive and negative symptoms of schizophrenia. Positive symptoms include delusions, hallucinations, and certain types of thought disorder; flat affect and other types of thought disorder are considered negative symptoms. These groups of symptoms are hypothesized to represent different underlying processes in the disease. In the present study, positive and negative symptoms and social competence were measured in 44 children at risk for schizophrenia, 38 children at risk for affective disorders (e.g., depression), and 62 matched normal children. The children were considered at-risk for a particular disorder, if they had a parent with that disorder. The study was longitudinal in design; at the first assessment, children were an average of 9 years old; at the second, they were an average of 12.3 years old; and at the third evaluation, they were an average of 15.4 years old; representing childhood, early adolescence, and adolescence, respectively. In childhood, there were no significant group differences on measures of social competence, negative symptoms, or positive symptoms as rated by standardized scales. By early adolescence, however, children at risk for schizophrenia began to show a deficit in social competence compared with the normal control children and the children at risk for affective disorders. They also had more positive thought disorders than children at risk for affective disorder, but they did not differ from normal children in this regard. There were no differences among the groups on negative symptoms. In adolescence, children at risk for schizophrenia maintained a relatively poor level of social competence compared with the other groups and had greater positive and negative symptoms. It is concluded that children at risk for schizophrenia are more likely than others to have social deficits in early adolescence and adolescence, and these children also have greater positive and negative symptoms in adolescence. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: The purpose of this study was to develop a clinician-based cognitive, psychoeducational, preventive intervention for families with parental affective disorder that would be suitable to widespread use, test its feasibility and safety, and define the areas affected by the intervention. The intervention was designed to increase understanding of parental illness and resilience in the children. Method: The authors studied the first seven families (14 parents) to receive the intervention. Enrollment criteria included affective disorder during the preceding year in at least one parent, presence of at least one child between the ages of 8 and 14 years who was not psychiatrically ill at the time of participation, and willingness to participate in the research study. The intervention consisted of parent, child, and family sessions. Assessment included semistructured interviews with parents about affective disorders, standard ratings of marital satisfaction and therapeutic alliance, and a recently developed semistructured interview to assess response to the intervention. Results: Overall satisfaction with the intervention was rated moderate to high by parents. No harm was reported. Ten of 14 parent subjects reported five or more behavior and attitude changes that they attributed to the intervention. The most frequent behavior and attitudinal changes reported were increased discussion of the illness and related issues and increased understanding of information about affective illness. Conclusions: The authors conclude that the intervention is safe and feasible in families with parental affective disorder.

Prodromal symptoms, or the signs and symptoms that precede a disorder and that are distinctly different from those found during the acute phase of the disorder, are important in medicine because early detection of illness is often crucial to favorable treatment and outcome. But in psychiatry, research on prodromal symptoms has been rare, with the exception of studies regarding schizophrenia. The current article surveys the literature with regard to the prodromal symptoms of affective disorders, such as depression, mania, and anxiety. Twenty-four studies were found that specifically addressed the issue of prodromal symptoms, and they were in agreement that the prodromal phase, at least for mania, depression, and panic attacks, may precede the full-blown acute phase of the illness by weeks and sometimes even months. For mania, the symptoms include headaches, weariness, lack of pleasure, irritability, and sleeplessness. The prodromal phase of depression varies. In sudden-onset depression there appear to be few prodromal symptoms. Gradual-onset depression is related to ongoing stress. Neurotic-onset depression is often preceded by anxiety disorders, and fluctuating-onset depression is characterized by symptoms that fluctuate in intensity before full-blown depression sets in. Symptoms during the prodromal phase of panic disorders have not been agreed upon. Some cite avoidance behavior as a sign, while others say that avoidance is caused by the panic disorder itself. If prodromal symptoms can be more clearly identified, treatment for these disorders could be initiated sooner and might be more effective. It is recommended that attention to prodromal symptoms compliment current standards of clinical assessment, namely the identification of symptoms during the acute phases of psychiatric disorders. Studies that have been completed on prodromal symptoms need to be updated as well, as most were carried out in the 1960s. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin. The authors examined whether polymorphisms A218C and A779C in intron 7 of the tryptophan hydroxylase gene are associated with a risk for affective disorders or suicidal behavior. Method: Subjects were 141 patients with bipolar disorder and 73 patients with unipolar affective disorder, 46 of whom had a history of attempted suicide, and 208 healthy volunteers. All subjects were unrelated to each other, and all were Japanese. Genotyping was performed by polymerase chain reaction amplification followed by digestion by a restriction enzyme and single-strand conformational polymorphism analysis. Results: There was no significant genotypic or allelic association of the A218C polymorphism with bipolar disorder, unipolar depression, or history of attempted suicide. In nearly 100% of the subjects, genotypes for the A779C were identical to those for the A218C. Conclusions: The authors conclude that the examined polymorphisms are unlikely to have major relevance to the pathogenesis of affective disorders or suicidal behavior.

Seasonal depression shares certain common symptoms with nonseasonal depression; however, the two disorders have never been examined in a single study, to the authors' knowledge. The goal of this research was to examine the potential similarities in cognitive impairments in seasonal affective disorder and major depressive disorder in college students in the Midwest. Identification of affective disorders was based on participants' self-reported behavior and affect on the Beck Depression Inventory and the Seasonal Pattern Assessment Questionnaire. A group of 93 participants was assessed for major depressive disorder and seasonal affective disorder in late autumn and completed the Cognitive Failures Questionnaire for reported diffi culties in everyday activities that correspond to problems with perception, attention, and memory retrieval. The results indicated that seasonal affective disorder was highly prevalent (28.0%), substantially more so than major depressive disorder (8.6%). Similar to previous research on major depressive disorder, gender differences were also evident among participants with seasonal affective disorder, with more women qualifying than men. Both affective disorders were associated with higher reports of cognitive failures in comparison to participants with no depressive symptoms. These results reveal that individuals with seasonal affective disorder showed cognitive impairments similar to those with nonseasonal depression.

The authors used the Wisconsin Card Sorting Test to study 50 hospitalized psychiatric patients: 28 with schizophrenia, 17 with affective disorders, and five with schizoaffective disorder. The schizophrenic patients performed significantly more poorly than the patients with affective disorders. Both groups of patients improved when given additional instructions. The schizophrenic patients maintained their improvement when retested approximately 6 weeks later. The results suggest that factors other than frontal cortex dysfunction are involved in schizophrenic patients' performance on the Wisconsin Card Sorting Test.

Objective: The authors' goal was to determine if the actual treatment of schizoaffective and bipolar affective disorders has changed in light of recent clinical drug trials that have suggested that valproate and carbamazepine may be equivalent in efficacy to lithium. Method: Medication utilization rates for each 6-month period from July 1, 1989, to June 30, 1994, were compiled from the clinical database of the Palo Alto Veterans Affairs Medical Center. Results: The use of valproate and valproate plus lithium was negligible in 1989. By 1994, these medication regimens accounted for 25% of the standard antimanic treatments used for bipolar affective disorder and 38% of the treatments used for schizoaffective disorder. Regimens of carbamazepine and carbamazepine plus lithium dropped from 24% of antimanic treatments in 1989 to 18% in 1994. From 1989 to 1994, there was a decline in the rate of lithium monotherapy for treatment of bipolar affective disorder (from 84% to 43%) and schizoaffective disorder (from 100% to 53%). Conclusions: In the past 5 years, valproate monotherapy has increased as a percentage of total antimanic pharmacotherapies, while lithium mono-therapy has declined.

Objective: The authors compared sustained attention deficits measured by the Continuous Performance Test in patients with various affective disorders and patients with schizophrenia and examined whether Continuous Performance Test deficits in patients with affective disorders improve with remission of affective disorder symptoms. Method: Patients with schizophrenia (N=41), major depression without psychotic features (N=22), bipolar disorder without psychotic features (N=22), and bipolar disorder with psychotic features (N= 46) completed Continuous Performance Test sessions with an undegraded version of the test and a 25% degraded version in which the stimulus images were visually distorted. Subjects were also interviewed with the Chinese version of the Diagnostic Interview for Genetic Studies. All inpatients with schizophrenia (N=41) and bipolar disorder (N=15) were assessed both at admission and discharge. Subjects' Continuous Performance Test scores were standardized in comparison with scores for a community sample of 345 subjects, with adjustment for age, sex, and level of education. Results: Compared with the general population, all patient groups except the group with nonpsychotic major depression were significantly impaired in their ability to discriminate target stimuli from nontarget stimuli on the Continuous Performance Test. Patients with schizophrenia had the severest impairment, followed by patients with bipolar disorder with psychotic features and those with bipolar disorder without psychotic features. From admission to discharge, Continuous Performance Test deficits in schizophrenia remained unchanged, but inpatients with bipolar disorder showed significant improvement on the degraded Continuous Performance Test. All patients adopted a similar response criterion (the amount of perceptual evidence the person requires to decide that a stimulus is a target) to that in the general population, except that the patients with schizophrenia had a less stringent response criterion during the degraded Continuous Performance Test. Conclusions: Continuous Performance Test deficits are stable vulnerability indicators for schizophrenia, mediating indicators for bipolar disorder, and state-dependent indicators for major depression.

Objective: This study ascertained the incidence of complications during pregnancy, labor, and delivery and the neonatal characteristics of infants born to women with schizophrenia, bipolar disorder, or major depression in a population-based cohort. Method: Based on records linkage across a psychiatric case register and prospectively recorded obstetric data, the study comprised women with schizophrenia or major affective disorders who had given birth to 3,174 children during 1980-1992 in Western Australia. A comparison sample of 3,129 births to women without a psychiatric diagnosis was randomly selected from women giving birth during 1980-1992. Complications were scored with the McNeil-Sjostrom Scale. Odds ratios were calculated for specific reproductive events. Results: Both schizophrenic and affective disorder patients had increased risks of pregnancy, birth, and neonatal complications, including placental abnormalities, antepartum hemorrhages, and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth population decile, and to have children with cardiovascular congenital anomalies. Neonatal complications were significantly more likely to occur in winter; low birth weight peaked in spring. Complications other than low birth weight and congenital anomalies were higher in pregnancies after psychiatric illness than in pregnancies preceding the diagnosis. Conclusions: While genetic liability and gene-environment interactions may account for some outcomes, maternal risk factors and biological and behavioral concomitants of severe mental illness appear to be major determinants of increases in reproductive pathology in this cohort. Risk reduction in these vulnerable groups may be achievable through antenatal and postnatal interventions.

Objective: Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant Iod scores of over 3.00. Several other linkage studies have found Iod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. Method: DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. Results: Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. Conclusions: These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.

Objective: A subpopulation of chronically mentally ill patients, sometimes referred to as 'revolving door' patients, are frequently readmitted to psychiatric units. This study examined the relationships among demographic features, diagnostic characteristics, and frequency of hospitalization of patients from four state hospitals. Method: Two semistructured, standardized instruments, the Schedule for Affective Disorders and Schizophrenia and a life events history, were administered to 135 inpatients who met the Research Diagnostic Criteria for schizophrenia (N=56), schizoaffective disorder (N=33), unipolar major depressive disorder (N=23), and bipolar disorder (N=23). Criminal history was assessed by arrest records. The main outcome measure was the number of hospitalizations. Results: Chi-square and trend test analyses indicated that substance abuse and noncompliance with medication regimens were significantly associated with higher frequencies of hospitalization. A multiple regression model, which included alcohol/drug problems, medication noncompliance, and six sociodemographic and diagnostic variables (age, gender, race, marital status, years of education, and diagnosis) accounted for a significant proportion of the ability to predict frequency of hospitalization. Half of this predictability was due to the relationship of substance abuse and medication noncompliance with number of hospitalizations. Conclusions: Alcohol/drug problems and noncompliance with medication were the most important factors related to frequency of hospitalization. Preventing these behaviors through patient education may reduce rehospitalization rates.

Schizoaffective disorder is characterized by symptoms of both schizophrenia and affective illness, which include mood disorders such as depression. Whether it is a form of schizophrenia or affective illness, part of a continuum of both, or a completely separate condition, remains a topic of debate. The approaches to solving this dilemma take a variety of directions, one of which is to compare the outcome of those with schizoaffective disorder, schizophrenia, and affective disorder. A group of 101 psychiatric patients were assessed, which was composed of 41 schizoaffective patients, 20 schizophrenics, 20 patients with bipolar illness, and 20 patients with major depressive illness. Functioning and overall adjustment were assessed for all patients at initial intake, two years after hospitalization, and four-to-five years after discharge. Overall, schizoaffective, schizophrenic, and bipolar patients functioned more poorly than depressives after discharge from the hospital. These results did not change over time; at two-year follow-up, depressed patients had the highest level of functioning, followed by those with bipolar disorder, subjects with schizoaffective disorder, and schizophrenics; at the second follow-up, this pattern remained the same. Overall, the outcome of schizoaffective patients was similar to both schizophrenics and those with affective disorders, making it likely that schizoaffective disorder is not just a variant of affective disorder. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: The current research was designed to investigate the relationship between affective disruption and psychosis in unipolar major depressive disorder and to evaluate whether some depressed patients are particularly vulnerable to subsequent psychosis. Method: A group of 31 psychotic and 63 nonpsychotic inpatients with unipolar depression were assessed during hospitalization and then prospectively assessed for depressive and psychotic symptoms 2.4 years after hospital discharge. Results: The psychotic depressed inpatients had significantly higher rates of psychosis during the posthospital period, 2.4 years later, than the originally nonpsychotic depressed inpatients. However, they did not have higher rates of depressive syndromes during the posthospital period. Psychosis during the posthospital period was significantly related to recurrent or persistent affective disruption. The posthospital depressive syndromes of the initially psychotic depressed inpatients tended to be slightly more severe than those of the initially nonpsychotic depressed inpatients. Despite this, psychosis during the inpatient period was more predictive of posthospital psychosis than the severity of the posthospital depressive syndrome. Conclusions: The interaction of the following two factors was proposed to be central to psychotic depression: 1) a vulnerability to psychosis, and 2) concurrent affective disruption.

Cyclothymia refers to the phenomenon of cyclic changes in mood, such as occur with manic depressive illness at the extreme ends of the mood spectrum. To assess relationships between cyclothymic mood swings and psychosocial adjustment, 38 depressed (unipolar), 27 manic depressive (bipolar) and 27 other psychiatric patients were studied four years after hospital discharge; a control group of 153 normal subjects was also included in the study. The patients had much greater mood swings than the control group, but among the patients, there were no significant differences. In terms of the ability to function and cope after hospitalization, the cyclothymic patients were much less adept than the other psychiatric patients. The findings suggest either that cyclothymia itself interferes with psychosocial function, or else cyclothymic mood swings result from a broader underlying factor that increases the probability of poor social functioning. The authors suggest the latter hypothesis is more likely, and indicate that minor mood swings in patients who have a hard time adjusting after psychiatric hospitalization may in fact be reflecting a persistent vulnerability to psychopathology.

Objective: In 1970, Guze and Robins published a meta-analysis of suicide in patients with affective illness that inferred a lifetime risk of 15%. Since then, this figure has been generalized to all depressive disorders and cited uncritically in many papers and textbooks. The authors argue for an alternative estimate of suicide risk and question the generalizability of the Guze and Robins estimate. Method: The authors sorted studies obtained through a literature search that included data pertaining to suicide occurrence in affective illness into one of three groups: outpatients, inpatients, or suicidal inpatients. Suicide risks were calculated meta-analytically for these three groups, as well as for two previously published collections. Results: There was a hierarchy in suicide risk among patients with affective disorders. The estimate of the lifetime prevalence of suicide in those ever hospitalized for suicidality was 8.6%. For affective disorder patients hospitalized without specification of suicidality, the lifetime risk of suicide was 4.0%. The lifetime suicide prevalence for mixed inpatient/outpatient populations was 2.2%, and for the nonaffectively ill population, it was less than 0.5%. Conclusions: The percentage of subjects dead due to suicide (case fatality prevalence) is a more appropriate estimate of suicide risk than the percentage of the dead who died by suicide (proportionate mortality prevalence). More important, it is well established that patients with affective disorders suffer a higher risk of suicide relative to the general population. However, no risk factor, including classification of diagnostic subtype, has been reliably shown to predict suicide. This article demonstrates a hierarchy of risk based on the intensity of the treatment setting. Given that patients with a hospitalization history, particularly when suicidal, have a much elevated suicide prevalence over both psychiatric outpatients and nonpatients, the clinical decision to hospitalize in and of itself appears to be a useful indicator of increased suicide risk. (Am J Psychiatry 2000; 157:1925-1932)

Objective: Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders. Method: From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods. Results: By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37.6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3.6-fold over the 8-year study period. Conclusions: Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. doi: 10.1176/appi.ajp.2010.10040541

Objective: To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. Method: Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. Results: While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. Conclusions: These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation. (Am J Psychiatry 2010; 167:61-69)

Objective: Genome scans have revealed significant evidence for linkage of depression to chromosome 15q25.3-q26.2. The gene for neurotrophic tyrosine kinase receptor 3 (NTRK3), the receptor for neurotrophin-3 (trkC) and a key gene in neurotrophin signaling, is located within this region and, given evidence for synaptic plasticity as a mechanism in mood disorders, was considered a prime candidate. The authors investigated NTRK3 as a susceptibility gene for childhood-onset mood disorders. Method: The study sample consisted of 603 families with 723 affected children and adolescents diagnosed with a mood disorder with onset of the first episode by age 15. The authors genotyped 18 polymorphic markers across the NTRK3 gene in this sample and tested for association. Results: Results identified significant evidence for association for five of the markers using the transmission disequilibrium test. Four of the five markers were located in a region of strong linkage disequilibrium and were highly correlated. Haplotype results provided significant evidence for association to haplotypes composed of markers located in two haplotype blocks. Conclusions: The results for NTRK3 as well as the authors' previous finding for association to brain-derived neurotrophic factor in this sample support synaptic plasticity as a mechanism contributing to mood disorders that begin during childhood and adolescence and specifically implicate the NTRK3 gene as a contributing factor in the 15q-linked region.

Objective: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrowphenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). Method: Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. Results: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrowphenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. Conclusions: Results indicate that while irritability is an important feature of severe mood dysregulation and narrowphenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.

Objective: Research on the workplace costs of mood disorders has focused largely on major depressive episodes. Bipolar disorder has been overlooked both because of the failure to distinguish between major depressive disorder and bipolar disorder and by the failure to evaluate the workplace costs of mania/hypomania. Method: The National Comorbidity Survey Replication assessed major depressive disorder and bipolar disorder with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and work impairment with the WHO Health and Work Performance Questionnaire. A regression analysis of major depressive disorder and bipolar disorder predicting Health and Work Performance Questionnaire scores among 3,378 workers was used to estimate the workplace costs of mood disorders. Results: A total of 1.1% of the workers met CIDI criteria for 12-month bipolar disorder (I or II), and 6.4% meet criteria for 12-month major depressive disorder. Bipolar disorder was associated with 65.5 and major depressive disorder with 27.2 lost workdays per ill worker per year. Subgroup analysis showed that the higher work loss associated with bipolar disorder than with major depressive disorder was due to more severe and persistent depressive episodes in those with bipolar disorder than in those with major depressive disorder rather than to stronger effects of mania/hypomania than depression. Conclusions: Employer interest in workplace costs of mood disorders should be broadened beyond major depressive disorder to include bipolar disorder. Effectiveness trials are needed to study the return on employer investment of coordinated programs for workplace screening and treatment of bipolar disorder and major depressive disorder.

Objective: This article is an overview of epidemiological and treatment studies suggesting that deficits in dietary-based omega-3 polyunsaturated fatty acids may make an etiological contribution to mood disorders and that supplementation with omega-3 fatty acids may provide a therapeutic strategy. Method: Relevant published studies are detailed and considered. Results: Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. Conclusions: Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach. This review identifies a number of hypotheses and studies for consideration. In particular, the authors argue for studies clarifying the efficacy of omega-3 supplementation for unipolar and bipolar depressive disorders, both as individual and augmentation treatment strategies, and for studies pursuing which omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is likely to provide the greatest benefit.

Objective: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. Method: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. Results: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. Conclusions: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely iii before treatment with fluoxetine.

Objective: Irritability is a widely occurring DSM-IV symptom in youths. However, little is known about the relationship between irritability in early life and its outcomes in mid-adulthood. This study examines the extent to which youth irritability is related to adult psychiatric outcomes by testing the hypothesis that it predicts depressive and generalized anxiety disorders. Method: The authors conducted a longitudinal community-based study of 631 participants whose parents were interviewed when participants were in early adolescence (mean age=13.8 years [SD= 2.6]) and who were themselves interviewed 20 years later (mean age=33.2 years [SD=2.9]). Parent-reported irritability in adolescence was used to predict self-reported psychopathology, assessed by standardized diagnostic interview at 20-year follow-up. Results: Cross-sectionally, irritability in adolescence was widely associated with other psychiatric disorders. After adjustment for baseline emotional and behavioral disorders, irritability in adolescence predicted major depressive disorder (odds ratio=1.33, 95% confidence interval [CI]=1.00-1.78]), generalized anxiety disorder (odds ratio=1.72, 95% CI=1.042.87), and dysthymia (odds ratio=1.81, 95% CI=1.06-3.12) at 20-year follow-up. Youth irritability did not predict bipolar disorder or axis II disorders at follow-up. Conclusions: Youth irritability as reported by parents is a specific predictor of self-reported depressive and anxiety disorders 20 years later. The role of irritability in developmental psychiatry, and in the pathophysiology of mood and anxiety disorders specifically, should receive further study.

'Marc' is a 15-year-old male who presents with his parents for evaluation because of significant symptoms of anxiety and depressed mood. Marc responds verbally when greeted in the waiting room but avoids eye contact. He has an above-average IQ, with significantly higher verbal than nonverbal abilities. Academic difficulties in elementary school led to a diagnosis at age 8 of nonverbal learning disability. Marc continues to struggle academically and is falling further and further behind in school. He has strong interests in the Titanic and baseball that involve recitation of facts, dates, and numbers. He will talk at length on these topics, often using language that is more formal than expected for his age, but he is unable to sustain conversations on other topics. Although Marc prefers to interact with adults, he does describe himself as having friends; later his parents reveal that he does not interact with peers outside of school, and when asked, Marc is unable to describe what it means to be a friend. Marc's parents are very concerned about the widening gap between Marc's social development and that of his peers. Marc's history includes perinatal problems, and his family history includes autism spectrum disorder.

Objective: This study examined the relation between the presence of depressive symptoms in schizophrenic patients with a recent first psychotic episode and affective disorders among their relatives. Method: Data on depressive symptoms in 70 patients with schizophrenia diagnosed according to the DSM-III-R criteria, who had had a recent first psychotic episode, and psychiatric diagnostic information on 293 of their first-degree and 674 of their second-degree relatives were collected. Depressive symptoms in the schizophrenic probands were examined at the index psychotic episode (at study entry) and systematically over a 1 -year follow-through period. The majority of first-degree family members were interviewed in person with the use of semistructured diagnostic interviews. Results: The linear regression findings confirmed the hypothesis that depressive symptoms in the early course of schizophrenia are associated with a family history of unipolar affective illness. Conclusions: Because depression in the patients was associated with a family history of depression, this suggests that depression in schizophrenia is not solely either a reaction to having had a psychotic episode or part of the recovery process. The findings are consistent with a model in which a familial genetic liability to affective disorder, when present, is viewed as exerting a modifying influence on the patient's schizophrenic illness to increase expression of depressive symptoms.

Objective: The purpose of this study was to examine the correlates and consequences of two constructs related to affective experience: neuroticism and affective instability. Method: One hundred thirty-two patients were assessed at intake for axis I and II symptoms, general personality traits, and specific impairments, including impairments in interpersonal functioning. The data included responses to structured and semistructured interviews, self-reports of interpersonal problems, and reports of interpersonal problems from significant others. Clinical ratings of axis I and II symptoms and of impairment were made by using the LEAD (i.e., longitudinal, expert, all data) consensus approach. Ninety-one of the 132 patients were reassessed at 12-month follow-up. Results: Neuroticism and affective instability manifested varied concurrent relations, with neuroticism being strongly related to an anxious, avoidant style and affective instability related to more externalizing personality styles. Prospectively, neuroticism predicted later symptoms, occupational impairment, and global dysfunction, whereas affective instability predicted romantic impairment. Conclusions: The findings suggest that neuroticism and affective instability--which are considered core aspects of personality pathology--are related but distinct constructs with unique correlates and different predictive abilities.

Objective: Observational studies suggest that long-term lithium treatment has a strong antisuicidal effect in mood disorders, but it is uncertain whether this association is a genuine therapeutic effect or is due to confounding factors in nonrandomized studies. The authors conducted a systematic review and meta-analysis of randomized trials to investigate the effect of lithium, compared to placebo and other active treatments, on the risk of suicide, deliberate self-harm, and all-cause mortality in patients with mood disorder. Method: The data source was the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE (1966-June 2002), EMBASE (1980-June 2002), CINAHL (1982-March 2001), PsycLIT (1974-June 2002), PSYNDEX (1977-October 1999), and LILACS (1982-March 2001). The Cochrane Central Register of Controlled Trials (CENTRAL) was searched with the term 'lithium' for new records entered into the database from 1999 to 2003. Studies selected included randomized, controlled trials comparing lithium with placebo or all other compounds used in long-term treatment for mood disorders (unipolar depression, bipolar disorder, schizoaffective disorder, dysthymia, and rapid cycling, diagnosed according to DSM or ICD criteria). Of 727 references identified in the search, 52 articles were marked as possibly relevant on the basis of the abstract, and 32 randomized, controlled trials were eligible for inclusion in the review. Two independent reviewers extracted the data, and disagreements were resolved by consensus with a third reviewer. Methodological quality was assessed according to the criteria of the Cochrane Collaboration. When the outcomes of interest were not reported, an attempt was made to obtain the required data from the original authors. Results: In 32 trials, 1,389 patients were randomly assigned to receive lithium and 2,069 to receive other compounds. Patients who received lithium were less likely to die by suicide (data from seven trials; two versus 11 suicides; odds ratio=0.26; 95% confidence interval [Cl]=0.09-0.77). The composite measure of suicide plus deliberate self-harm was also lower in patients who received lithium (odds ratio= 0.21; 95% Cl = 0.08-0.50). There were fewer deaths overall in patients who received lithium (data from 11 trials; nine versus 22 deaths; odds ratio=0.42, 95% Cl = 0.21-0.87). Conclusions: Lithium is effective in the prevention of suicide, deliberate self-harm, and death from all causes in patients with mood disorders.

Objective: The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders. Method: The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category. Results: Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size= -0.01, 95% CI=0.36 to 0.34). Conclusions: Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders.

Objective: Aberrant synaptic connectivity may underlie the involvement of the hippocampus in schizophrenia. There is reasonable neuropathological evidence for a presynaptic pathology but few studies of the postsynaptic component. This study tested the hypothesis that hippocampal dendritic pathology is also present in schizophrenia. Method: Using in situ hybridization in sections of hippocampal formation from 10 patients with schizophrenia, 10 patients with mood disorders (three with bipolar disorder and seven with major depression), and 10 healthy comparison subjects, the authors examined the expression of two important dendritic genes: spinophilin, which serves as a marker of dendritic spines, and microtubule-associated protein 2 (MAP2), an overall dendritic marker. Results: The patients with schizophrenia had lower levels of spinophilin mRNA in CA4 (hilus), CA3, the subiculum, and the entorhinal cortex than did the normal comparison subjects. The mood disorder group showed similar differences from the comparison group. MAP2 and cyclophilin mRNA did not differ between the groups in any subfield. Conclusions: Decreased spinophilin but unchanged MAP2 expression provides molecular evidence for a hippocampal dendritic pathology in schizophrenia that preferentially affects the spines. As spines are the target of most glutamatergic synapses, the data extend the evidence that excitatory synapses are particularly affected. Similar dendritic spine pathology may also occur in mood disorders.

Objective: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders. Method: Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain. Results: There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects. Conclusions: The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.

Objective: This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. Method: The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as 'temperamental' features related to mood dysregulation. Results: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. Conclusions: The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.

Objective: Antidepressants that inhibit the reuptake of serotonin (SSRIs) or norepinephrine (SNRIs) are effective in the treatment of disorders such as depression and anxiety. Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders, but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information. The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers. Method: Forty-two male and female volunteers were randomly assigned to 7 days of double-blind intervention with the SSRI citalopram (20 mg/day), the SNRI reboxetine (8 mg/day), or placebo. On the final day, facial expression recognition, emotion-potentiated startle response, and memory for affect-laden words were assessed. Questionnaires monitoring mood, hostility, and anxiety were given before and after treatment. Results: In the facial expression recognition task, citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear. Citalopram also abolished the increased startle response found in the context of negative affective images. Both antidepressants increased the relative recall of positive (versus negative) emotional material. These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety. However, reboxetine decreased subjective ratings of hostility and elevated energy. Conclusions: Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers, reducing the processing of negative relative to positive emotional material. Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression.

Objective: The authors analyzed data from a family sample ascertained for a genetic linkage study of bipolar disorder to address the following questions: Do the major clinical subtypes of familial affective disorder have distinct distributions of age at onset? What factors other than clinical subtype affect these distributions? After controlling for these factors, do the differences in age at onset persist among the subtypes? Method: Eighty-two families were ascertained through a treated proband with bipolar disorder who had a family history of two or more affected siblings or one affected sibling and one affected parent. After participating in an interview conducted by a psychiatrist using the Schedule for Affective Disorders and Schizophrenia - Lifetime Version, 274 probands and their first-degree relatives were diagnosed as having bipolar I, bipolar II, or recurrent unipolar disorder according to Research Diagnostic Criteria. Age at first major affective episode and other clinical data were collected. Results: Onset age distributions were similar for bipolar I and bipolar II disorder but significantly different for recurrent unipolar disorder. This finding persisted after adjustment for a significantly earlier onset among females. Subjects with affective disorder in both parental lines (bilineal) also experienced a significantly earlier onset. Substance abuse, physical illness, and sex of the affected parent had no significant impact on onset age. Conclusions: Although differences in age at onset may reflect several factors, these results provide indirect support for the view that bipolar I and bipolar II disorders are genetically related phenotypes and suggest that bilineal families may be more complex than previously assumed.

Objective: A modified autonomous response (e.g., electrodermal activity) in subjects with alexithymia (a reduced ability to identify and communicate emotions) while processing emotional information is well known. However, the functional and neurobiological bases of this impairment are unclear. Do subjects with alexithymia suffer from a primary lack of perception ('emotional blindness'), or is alexithymia based on incomplete information processing due to immature undifferentiated cognitive schemes? The study investigates if subjects with alexithymia show a modified central response as a correlate of classifying emotional aversive stimuli. Method: Twenty subjects with high alexithymia and 20 with low alexithymia (selected by the 20-item Toronto Alexithymia Scale) were investigated within a modified odd-ball paradigm. Three different stimulus categories were presented: aversive (probes) and affective neutral pictures (nontargets and instructed targets). Visual event-related EEG potentials and subjective data were recorded. Results: All subjects showed elevated positive amplitudes or mean activity after probe presentation in the latency range: 150-260, 280-450, and 600-1500 msec. Subjects with alexithymia displayed increased positive components (especially P2) of visual event-related potentials after probe presentation than subjects without alexithymia. Subjects without alexithymia more frequently verbalized the emotional impact of these aversive pictures than subjects with alexithymia. Conclusions: These findings do not support the assumption of a primary lack of perception in alexithymia. Subjects with alexithymia show central correlates of perception and classification of aversive pictures. They may need more effort and cognitive recourses to process emotional information. Nevertheless, spontaneous verbal reference to emotional stimulus aspects is reduced.

Objective: The goal of this study was to predict the onset of mood and anxiety disorders from parent-reported emotional and behavioral problems in childhood across a 14-year period from childhood into young adulthood. Method: In 1983, parent reports of behavioral and emotional problems were obtained with the Child Behavior Checklist for children and adolescents 4-16 years of age from the Dutch general population. At follow-up 14 years later, lifetime mood and anxiety diagnoses were obtained by a standardized DSM-IV interview for 1,580 subjects. Cox proportional hazards models were used to predict the incidence of mood and anxiety disorders from childhood problems and demographic covariates. Results: Mood disorders were significantly predicted by high scores on the anxious/depressed scale and on the internalizing composite (withdrawn, somatic complaints, and anxious/depressed). Anxiety disorders were significantly predicted by the social problems scale and the externalizing composite (delinquent behavior and aggressive behavior). Anxiety disorders predominantly started in childhood and early adolescence, whereas the incidence of mood disorders increased sharply in adolescence and young adulthood. Conclusions: These results suggest different developmental pathways for mood and anxiety disorders. The predictions based on problem behavior remained stable during the 14-year period across adolescence and young adulthood. The results therefore underline the importance of early intervention and prevention of behavioral and emotional problems in childhood. (Am J Psychiatry 2003; 160:2116-2121)

Objective: An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology--microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once. Method: This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed. Results: New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies. Conclusions: Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.

Objective: In subjects with mood disorders, positron emission tomography (PET) with [[sup.18]F]fluorodeoxyglucose has shown prefrontal cortical metabolism deficits, including in a subgenual region in subjects with familial illness. The authors applied a dl-fenfluramine challenge method to study metabolic response in this region to serotonergic challenge in familial major depression. Method: The study group consisted of 19 depressed subjects with major depressive disorder or bipolar disorder, all of whom had at least one first-degree relative with history of major depression, and 10 healthy volunteers with similar age and gender distributions. PET images were acquired under placebo and challenge conditions, and volumetric MRI scans were also obtained. Group comparisons of metabolic and volumetric data were performed. Ratings of acute mood change during serotonergic challenge were compared with the imaging data. Results: Within Brodmann's area 32, a glucose metabolism deficit in the depressed subjects on placebo day was observed by voxel-level analysis, but no volumetric deficit was found in the sub-genual regions examined. Under challenge, both groups suppressed metabolism similarly. Within the patient group, the correlation between acute mood improvement during challenge and greater metabolic suppression approached significance. Conclusions: In familial mood disorders, a ventromedial prefrontal cortical deficit in baseline metabolism is not due to altered structural volume, and the response to serotonergic challenge appears predictive of acute mood response. The potential to predict treatment response can be tested by a combined challenge and treatment study.

Objective: The hypothesis that human cocaine users lose vesicular monoamine transporter (VMAT2) protein was tested in striatal samples from cocaine users and age-, sex-, and postmortem interval-matched comparison subjects. Method: Striatal samples were retrieved at autopsy; immunoblot assays were then performed by using a highly specific VMAT2 antibody. Striatal radioligand binding to VMAT2 was assessed with dihydrotetrabenazine ([3H]DTBZ) and dopamine levels employing high-performance liquid chromatography. Results: Cocaine users displayed a marked reduction in VMAT2 immunoreactivity as well as reduced [[sup.3]H]DTBZ binding and dopamine levels. It did not appear that the reduction in VMAT2 immunoreactivity was related to ethanol use, but dopamine levels were lower in subjects with only ethanol diagnoses. Subjects suffering from cocaine-induced mood disorders displayed a greater loss of VMAT2 immunoreactivity that approached significance. Conclusions: Human cocaine users lose VMAT2 protein, which might reflect damage to striatal dopamine fibers. These neuronal changes could play a role in causing disordered mood and motivational processes in more severely dependent patients.

Early clinical observations and recent systematic studies overwhelmingly document a greater role for psychosocial stressors in association with the first episode of major affective disorder than with subsequent episodes. The author postulates that both sensitization to stressors and episode sensitization occur and become encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episodes themselves can induce the protooncogene c-fos and related transcription factors, which then affect the expression of transmitters, receptors, and neuropeptides that alter responsivity in a long-lasting fashion. Thus, both stressors and episodes may leave residual traces and vulnerabilities to further occurrences of affective illness. These data and concepts suggest that the biochemical and anatomical substrates underlying the affective disorders evolve over time as a function of recurrences, as does pharmacological responsivity. This formulation highlights the critical importance of early intervention in the illness in order to prevent malignant transformation to rapid cycling, spontaneous episodes, and refractoriness to drug treatment. (Am J Psychiatry 1992; 149:999-1010)