Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Assessing anhedonia in psychiatric patients.

In two studies of depressed, manic, schizophrenic, and normal subjects, a scale for measuring the intensity of subjects' pleasureable responses to normally emjoyable situations (the Pleasure Scale) evidenced good internal reliability and moderate agreement with the Chapman Anhedonia Scale and Indexes of depressive symptom severity. Only the depressed patients showed extremely anhedonic responses. Although more than half the depressed patients evidenced pleasure scores in the normal range, about 185 of them seemed more anhedonic than any norma subject. A mixture analysis resolved depressed patient scores into two distinct distributions: a normal-range distribution (88% of depressives) and an extremely anhedonic distribution (12%). The findings provide some support for the existence of a qualitatively distinct subtype of major depression that has been variously defined an "endogenomorphic" or "melancholic."

Differences between anhedonic and normally hedonic depressive states.

In this study of 101 patients who met DSM-III criteria for major depression, those with extreme anhedonia (N = 23) were younger, more depressed, and less neurotic than the patients with a normal-range capacity for pleasurable experiences (N = 78). The anhedonic depressed patients recovered more rapidly; at discharge they consequently had levels of symptom severity equal to those of the hedonic patients, yet they remained significantly more anhedonic. The anhedonic patients exhibited loss of pleasure in appetite, sex, social contacts, and work, which suggests a global dulling of the capacity for pleasure.

Interactions of risk factors in predicting suicide.

The authors examined interactions among risk factors for suicide, a strategy not typically followed in suicide research. Their results suggest an explanation for gender differences in suicide rates and qualifications in the relationship between hopelessness and suicide based on history of drug and alcohol abuse.

A field test of Motto's risk estimator for suicide.

The authors undertook a field test of Motto and colleagues' Risk Estimator for Suicide by selecting a subset (N = 593) of psychiatric patients with major or chronic affective disorder that corresponded to Motto's sample. They rated each subject on Motto's scale, using standardized data collected at hospital admission. Fourteen patients (2.4%) in their sample and 136 (4.9%) in Motto's sample died by suicide within 2 years. The authors tested the null hypothesis of a uniform suicide risk across all 10 deciles of risk scores by comparing observed and expected frequencies of suicide using the variance test for homogeneity of the binomial distribution. Their findings raise questions about Motto's risk scale but do not definitively invalidate it.

Depression and panic attacks: the significance of overlap as reflected in follow-up and family study data.

Ninety-one patients with panic attacks limited historically to depressive episodes had more severe depressive symptoms and were less likely to recover during a 2-year follow-up than 417 depressed patients who did not have panic attacks. Family study data clearly distinguished another 15 patients with panic disorder and secondary depression; interviewed relatives of panic disorder patients were significantly less likely to have primary depression and significantly more likely to have various anxiety disorders. These data support the hierarchical system by which many of the contemporary diagnostic systems separate panic disorder and major depression.

Lithium discontinuation and subsequent effectiveness.

OBJECTIVE: Several reports have raised concern that the discontinuation of lithium may result in treatment resistance following recurrence of affective disorder. This report explores this possibility. METHOD: The data derive from a large, naturalistic follow-up of patients with major depressive disorder or mania. Twenty-eight of the patients in the study were free of lithium and experiencing an episode of mania or schizoaffective mania diagnosed according to Research Diagnostic Criteria when they entered the study, recovered while taking lithium, later experienced a recurrence while not taking lithium, and then resumed lithium treatment. Survival analyses of time to recovery and, subsequently, time to recurrence, used continued lithium treatment as an additional censoring variable. RESULTS: Patients given lithium recovered no more quickly from their index episode than they did from their first prospectively observed episode. Moreover, lithium prophylaxis appeared no less effective after the first prospectively observed episode than after the index episode. CONCLUSIONS: These findings provide no evidence that lithium discontinuation results in treatment resistance when lithium is resumed.

Time-related predictors of suicide in major affective disorder.

The authors studied 954 psychiatric patients with major affective disorders and found that nine clinical features were associated with suicide. Six of these--panic attacks, severe psychic anxiety, diminished concentration, global insomnia, moderate alcohol abuse, and severe loss of interest or pleasure (anhedonia)--were associated with suicide within 1 year, and three others--severe hopelessness, suicidal ideation, and history of previous suicide attempts--were associated with suicide occurring after 1 year. These findings draw attention to the importance of 1) standardized prospective data for studies of suicide, 2) assessment of short-term suicide risk factors, and 3) anxiety symptoms as modifiable suicide risk factors within a clinically relevant period.

Reliability of lifetime diagnoses and symptoms in patients with a current psychiatric disorder.

In this study we assess the reliability of rating past psychiatric symptoms and lifetime diagnoses in a currently ill population using the SADS and RDC. Five raters from different centers interviewed 25 subjects in a short-interval test-retest design. Subjects had a wide diversity of affective and non-affective diagnoses and high levels of manifest psychopathology. Our results demonstrate that it is possible for raters from different research centers to reliably rate lifetime diagnoses and previous symptoms. Two important exceptions to the high reliability are the lifetime diagnoses of hypomania and the recurrent unipolar subtype of major depressive disorder, and we alert clinicians and researchers to be cautious when diagnosing these conditions. We conclude that the next step in measuring reliability should be a long-interval test-retest design with separate interviews conducted at the later assessment, one by the original rater and the other by a blind rater.

What is the mechanism by which suicide attempts predispose to later suicide attempts? A mathematical model.

A state dependence model of serial behavior suggests that each occurrence increases the subsequent likelihood of that behavior being repeated. A heterogeneity model, by contrast, suggests that the likelihood of a behavior occurring is predetermined, and uninfluenced by intervening occurrences. We have applied the random-effects probit model of Gibbons and Bock (1987) to examine the fit of the state dependence and heterogeneity models to longitudinal data on suicide attempts by 928 patients with affective disorder. Heterogeneity but not state dependence was required to model these data. The findings suggest that when considering patients with moderate to severe major affective disorder, the clinician should not interpret the absence of any recent suicide attempts to mean that the patient is at relatively low risk for attempting suicide in the future. An implication of the heterogeneity model is that suicide attempts made many years ago may have equal value to recent attempts when estimating an individual's "predisposition" to nonlethal attempts in the future.

Sex differences in the lifetime prevalence of depression: does varying the diagnostic criteria reduce the female/male ratio?

Most studies report the lifetime prevalence of major depressive disorder to be higher among women than men. One possible explanation is that this finding is the result of the diagnostic criteria used, in particular the inclusion of criterion symptoms associated with depressed mood. The number of criterion symptoms required for a diagnosis were varied and applied to 2163 first-degree relatives of affectively disordered probands of the NIMH Collaborative Study of the Psychobiology of Depression. Results indicated that differences between men and women in number of symptoms reported could not account for the difference in rates of depression. Women had a greater number of associated symptoms only at higher symptom levels, suggesting an excess of women only above a diagnostic threshold. Thus, findings supported a true difference in rates of major depressive disorder rather than a general trend for women to remember or report more criterion symptoms.

Concordance of symptoms in recurrent depressive episodes.

The presence or absence of 12 depressive symptoms was examined in 93 bipolar and 108 unipolar patients who had two discrete episodes of major depression over a 5-year period. For each symptom the concordance of its presence or absence across episodes was low. The agreement observed was largely that to be expected by chance. A substantial amount of concordance was obtained if differences in episode intensity (propensity to have symptoms) were taken into account. This suggests that although there may be factors related to depression which remain stable across episodes, symptom presentation is moderated by other factors, such as intensity, which vary from episode to episode.

Lack of stability of the RDC endogenous subtype in consecutive episodes of major depression.

The stability of the endogenous subtype of major depressive disorder was examined within individuals across consecutive episodes. The subjects were 119 probands from the NIMH Collaborative Depression Study who experienced at least two episodes of unipolar major depressive disorder within a two-year period of biannual evaluations. Structured data collection methods and Research Diagnostic Criteria were employed. The inter-episode stability of subtype diagnosis was low, never producing a kappa of greater than 0.25. This result was not attributable to threshold for diagnosis, time between episodes, differences in severity, or changes in raters.

The assessment and management of the suicidal patient.

This chapter will be oriented toward the problem faced by the clinician in attempting to prevent suicide in patients under treatment. It will focus on the clinician's difficult task of assessing suicide potential and initiating interventions to prevent suicide in patients at high risk. Specifically, the state of the art in identifying the suicidal patient will be reviewed, and various interventions available to the clinician will be discussed.

Relationship of electroconvulsive therapy to course in affective illness: a collaborative study.

Bipolars treated with electroconvulsive therapy (ECT) during the index episode were matched on the variables of age, sex, previous admissions and previous hospitalizations with 23 bipolars who did not receive ECT. A similar match was made for 42 unipolars who were under the age of 40 at time of admission. All patients were followed for 5 years. Those patients treated with ECT, both bipolars and unipolars, had the same numbers of episodes in follow-up as their matched groups. However, in both bipolar and unipolar ECT-treated patients, there were more follow-up rehospitalizations. The reason for this is not known but three possibilities exist. Successful treatment with ECT may make the family and patient more prone to consider rehospitalization. Secondly, the originally treated ECT patients may have had more aggressive doctors who were more likely to rehospitalize. Finally, ECT may change the course of an individual's illness in such a way that more severe episodes occur and rehospitalizations are necessary. The findings suggest the need for long-term studies following ECT on clinical and biological variables.

Gender differences in the clinical features of unipolar major depressive disorder.

Gender differences in the presence or absence and the severity of forty-seven clinician-rated features of depression were examined, controlling for the sex of the rater. Subjects consisted of 498 moderately to severely depressed patients coming for treatment and diagnosed as suffering from nonpsychotic, unipolar major depressive disorder. Significant differences were found only for increased appetite and weight. No differences were observed in endogenous symptoms, global severity of depression, or impairment in functioning. The results indicate that, although the rate of major depressive disorder is greater in women, its symptomatology is relatively homogeneous with regard to gender.

Association between major depressive disorder and physical illness.

The association between major depressive disorder (MDD) and self-reported histories of specific physical illnesses was investigated in 320 controls and 1968 first-degree relatives and 254 spouses of probands in the NIMH Collaborative Depression study. The Schedule for Affective Disorders and Schizophrenia-Lifetime Version was used to assign Research Diagnostic Criteria (RDC) diagnoses and a structured self-report instrument was used to assess lifetime medical history. Lifetime MDD was diagnosed in 914 subjects, 402 of whom had been hospitalized or received somatic treatment ('treated' MDD). Strong associations were observed between MDD (either treated or untreated) and both frequent/severe headaches and migraine headaches. There was a marked gender effect such that the relative odds for a woman with treated MDD to report migraine were over 5:1. Other associations were found between MDD and skin infections, respiratory illness, ulcer, hypotension, and diabetes. This is the largest non-patient sample using standardized assessment of mental disorders by direct interview in which associations between specific physical illnesses and MDD have been demonstrated. Implications for clinical practice and neurobiological research in depression are discussed.