Theodore Reich

Postpartum psychoses in patients with manic depressive disease.

From a consecutive series of 61 manic depressive patients a group of 20 bipolar manic depressive mothers and 29 female first degree relatives who had children and an episodic affective disorder were examined with respect to their postpartum state. The frequency of postpartum breakdowns was significantly greater than the frequency of nonpuerperal episodes during the period at risk of 15 to 80 years and during the childbearing years. Postpartum episodes followed 30 per cent of births of the patient group and 20 per cent of the births of the family group. Forty per cent of the patients with children and 41 per cent of the family members with children and affective disorder had a postpartum episode. These rates are much higher than population rates. After the first episode of manic depressive illness, the rates for postpartum illness were 50 per cent in the patient group and 25 per cent in the family group, suggesting that careful observation and early treatment is indicated. Eighty-three per cent of the postpartum episodes occurred during the 2 months following parturition and the symptoms during these episodes were similar to nonpuerperal manias and depressions.

Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies

The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.

Age-period-cohort analysis of secular trends in onset of major depression: Findings in siblings of patients with major affective disorder

Analyses of data from the NIMH-CRB Collaborative Depression Study on age at onset of Major Depressive Disorder (MDD) in 1144 directly interviewed siblings of patients with major affective disorder show a strong secular trend toward increased lifetime risk and earlier onset in successive cohorts of birth since 1930. The proportionate increases in the instantaneous probabilities (hazard) of onset of MDD for each one year difference in year of birth were 5% for brothers and 7% for sisters. Age-period-cohort analysis suggests a powerful period effect may be responsible for this secular trend in rates of MDD, with rates of onset for siblings between 15 and 50 years of age doubling between the 1960s and 1970s. Possible artifacts are investigated.

Cerebral cortical and white matter reactivity to carbon dioxide.

We measured cerebrovascular reactivity to carbon dioxide in the cerebral cortex and the subcortical white matter of 12 healthy adult volunteers (four young subjects aged 21-24, four middle-aged subjects aged 34-40, and four elderly subjects aged 62-85 years). Blood flow was computed from the concentration history of xenon-133 in the volume of interest measured with an ultrapure germanium detector array. End-tidal PaCO2 ranged from 35.4 to 42.6 mm Hg. The mean +/- SD baseline blood flows in the cerebral cortex were 60 +/- 7, 51 +/- 9, and 33 +/- 4 ml/100 cm3/min in the young, the middle-aged, and the elderly subjects, respectively; the corresponding subcortical white matter baseline blood flows were 21 +/- 1, 22 +/- 3, and 16 +/- 5 ml/100 cm3/min. Mean +/- SD cerebrovascular reactivities to carbon dioxide in the cerebral cortex were 2.03 +/- 0.58, 1.36 +/- 0.41, and 0.72 +/- 0.19 ml/100 cm3/min/mm Hg PaCO2 for the young, the middle-aged, and the elderly subjects, respectively; the corresponding reactivities in the subcortical white matter were 0.69 +/- 0.11, 0.59 +/- 0.17, and 0.36 +/- 0.41 ml/100 cm3/min/mm Hg PaCO2. Blood flow and cerebrovascular reactivity in the cerebral cortex of the young subjects were significantly higher than those for white matter and significantly higher than those in the elderly subjects (p less than 0.001). Age vs. blood flow (for the cortex) and age vs. cerebrovascular reactivity (for both cortical gray and subcortical white matter) also showed significant linear correlation (p less than 0.05). However, the age-related changes in white matter blood flow and cerebrovascular reactivity were slow, and the differences among the age groups were not statistically significant.

Solvent use as a precursor to intravenous drug abuse

Intravenous drug abuse (IVDA) is a significant public health threat, and ways of identifying individuals at high risk for IVDA are needed to plan strategies for intervention and treatment. Previous work had identified similarities in psychiatric diagnosis and patterns of drug use in IVDAs and solvent users. Using the same population, we found that 59 of 179 IVDAs (33.0%) reported a history of solvent use, which preceded the onset of IVDA in 41 of the 59. IVDAs with a history of solvent use were more likely to receive diagnoses of alcoholism and antisocial personality disorder (ASP) than IVDAs without solvent use. Even allowing for these coexisting psychiatric disorders, a reported history of solvent use increased the likelihood of also reporting IVDA by a factor of 3.2. Although the magnitude of risk is likely to differ in other populations, a history of solvent use may indicate individuals at high risk for IVDA, and youths who have used solvents should be considered at high risk for severe drug abuse, including IVDA.

General causal models for sex differences in the familial transmission of multifactorial traits: An application to human spatial visualizing ability

A general multifactorial model is given for the inheritance of traits that exhibit a sexual dimorphism. The model allows for polygenic inheritance, cultural transmission, phenotypic assortative mating, and a common environment of rearing. Several cultural mechanisms are described for which transmission from parent to offspring is sex-dependent and for which many different patterns of sex-specific correlations can result. A special case of the general model is described in which phenotypic differences between males and females are due only to differences in nontransmissible environmental factors and/or genetic factors that do not contribute to variability within a sex. Application of these models to human spatial visualizing ability, using data reported by others, gives an estimate of 45 per cent for the proportion of the variance that is accounted for by transmissible factors. Neither an X-linked hypothesis nor a sex-specific cultural mechanism is required to explain the transmission of spatial ability.

Segregation and linkage analyses of bipolar and major depressive illnesses in multigenerational pedigrees

Data were collected on six large multigenerational pedigrees, four ascertained through a proband with major depression and two ascertained through a proband with a bipolar form of illness. Diagnoses were made using the SADS-L structured interview and Research Diagnostic Criteria (RDC). Complex segregation analyses were conducted on the bipolar and the major depression pedigree sets using a model allowing for both major locus and polygenic inheritance; in these analyses a variety of diagnostic schemes and assumptions concerning the lifetime population prevalence were examined. Linkage analyses on standard markers were conducted using parameters for transmission of susceptibility to illness derived from the segregation analyses. Results of the segregation analyses were quite sensitive to the diagnostic and prevalence assumptions. In the pedigrees ascertained through probands with a bipolar form of illness, we were unable to discriminate between major gene and polygenic inheritance. The data were compatible with Mendelian major gene transmission of susceptibility to illness when bipolar and schizoaffective manic diagnoses were considered as affected and the lifetime population prevalence was between 0.04 and 0.06. Outside this narrow prevalence range, or when additional diagnoses, such as major depression or hypomania, were included as expressions of liability to disease, major gene transmission of susceptibility to disease could be rejected. Similarly, in the pedigrees ascertained through probands with major depression, it was not generally possible to discriminate between major gene and polygenic transmission of susceptibility to illness. For a diagnostic scheme including only major depression as a manifestation of susceptibility to illness, there was a narrow range of lifetime population prevalence values (female prevalence ranging from 0.20 to 0.25, male prevalence set to 1/2 female prevalence) which yielded results compatible with major gene transmission. Linkage analyses for all markers yielded negative or inconclusive results. In one bipolar pedigree a lod score of 1.65 was found with a marker in chromosome 1 recommending further studies of this chromosome.

Power Loss for Linkage Analysis due to the Dichotomization of Trichotomous Phenotypes

Objectives: Some traits, while naturally polychotomous, are routinely dichotomized for genetic analysis. Dichotomization, intuitively, leads to a loss of power to detect linkage, as some phenotypic variability is discarded. This paper examines this power loss in the context of a trichotomous trait. Methods: To examine this power loss, we performed a simulation study where a trichotomous trait was simulated in a sample of 1,000 sib-pairs under various genetic models. The study was replicated 1,000 times. Linkage analysis using a variance components method, as implemented in Mx, was then performed on the trichotomous trait and compared with that on a dichotomized version of the trait. Results: A comparison of the power and false positive rates of the analyses shows that power to detect linkage was increased by up to 22 percentage points simply by examining the trait as a trichotomy instead of a dichotomy. Under all models examined, the trichotomous analysis outperformed the dichotomous version. Conclusions: Comparable levels of false positive rates under both methods confirm that this power gain comes solely from the information lost upon dichotomization. Thus, dichotomizing tri- or poly-chotomous traits can lead to crippling power loss, especially in the case of many loci of small effect.

Genetic association of bipolar disorder with the β3 nicotinic receptor subunit gene

Objective Owing to the clinical relationship between bipolar disorder and nicotine dependence, we investigated two research questions: (i) are genetic associations with nicotine dependence different in individuals with bipolar disorder as compared with individuals without bipolar disorder, and (ii) do loci earlier associated with nicotine dependence have pleiotropic effects on these two diseases. Method Our study consisted of 916 cases with bipolar disorder and 1028 controls. On the basis of known associations with nicotine dependence, we genotyped eight single-nucleotide polymorphisms (SNPs) on chromosome 8 (three bins) in the regions of CHRNB3 and CHRNA6, and six SNPs on chromosome 15 (three bins) in the regions of CHRNA5 and CHRNA3. Results To determine whether the genetic associations with nicotine dependence are different in bipolar disorder than in the general population, we compared allele frequencies of candidate SNPs between individuals with nicotine dependence only and individuals with both nicotine dependence and bipolar disorder. There were no statistical differences between these frequencies, indicating that genetic association with nicotine dependence is similar in individuals with bipolar disorder as in the general population. In the investigation of pleiotropic effects of these SNPs on bipolar disorder, two highly correlated synonymous SNPs in CHRNB3, rs4952 and rs4953, were significantly associated with bipolar disorder (odds ratio 1.7, 95% confidence interval: 1.2–2.4, P=0.001). This association remained significant both after adjusting for a smoking covariate and analyzing the association in nonsmokers only. Conclusion Our results suggest that (i) bipolar disorder does not modify the association between nicotine dependence and nicotinic receptor subunit genes, and (ii) variants in CHRNB3/CHRNA6 are independently associated with bipolar disorder.

Ascertainment Bias for Non-Twin Relatives in Twin Proband Studies!

When families are ascertained through affected twins, as for example when twin probands are selected from a registry and their non-twin relatives studied, a correction for ascertainment bias is needed. It is shown that probandwise counting (where relatives of doubly ascertained twin pairs are counted twice) is the appropriate method. The bias resulting from pairwise counting is given and depends on the genetic model and on the probability of selecting an affected twin as a proband. For the multifactorial and generalized single major locus models the bias is small, and the problems associated with nonindependent ascertainment are negligible in practice.