Familial subtypes of unipolar depression: a prospective study of familial pure depressive disease compared to depression spectrum disease.

In a large multicenter effort, major depressives were systematically studied at index admission and prospectively followed up for 5 years. Primary unipolar depressives with a family history of alcoholism (depression spectrum disease) differ from depressives with a family history of depression only (familial pure depressive disease) in having more familial anxiety and somatization disorder, more divorce, more suicide attempts, more negative life events, and needed more time to recover from the index episode. In the 5-year follow-up they are more likely to develop alcoholism and drug abuse. Depressive spectrum disease patients are more likely to meet systematic criteria for neurotic depression. The data suggest that major depression is a syndrome that is heterogeneous, and may be a final common pathway of more than one familial illnesses.     

Possible linkage between group-specific component (Gc protein) and pure depressive disease.

Genetic linkage was studied in pure depressive disease, a subgroup of unipolar depression defined by absence of familial alcoholism and/or antisocial personality. Rigorous research criteria were used for diagnosis and the diagnoses were made blind, i.e. without the knowledge of the genetic marker results. Under the assumptions of full penetrance and of all examined individuals' having passed the risk period, two out of eight families investigated showed a possibility of linkage, using the lod score method, with the Group-Specific Component (Gc protein) locus, one of the 17 polymorphic markers tested. The results, being based on a small amount of data, are presented as a hypothesis only; important possible implications of Psychiatry, however, indicate the desirability of testing the hypothesis.     

Linkage analysis of pure depressive disease

In a study of the subgroups of unipolar affective disease, 13 families were ascertained as pure depressive disease (PDD) families. Here we investigate linkage relationships between PDD and 30 genetic markers in these families. Using the robust sib-pair method of linkage analysis, evidence for possible linkage or association was found with five loci: the ABO and MNS blood groups, immunoglobulin kappa (IGK), proline rich parotid salivary protein (PR) and glyoxylase-1 (GLO1). Weak evidence of linkage with ABO was supported using the lod score method of analysis. The maximum lod score between PDD and ABO was 1.42 at a male recombination fraction of 0.09 and a female recombination fraction of 0.03. When these results from the sib-pair analysis were combined with the results from two previous sib-pair studies on PDD, the ABO, MNS and IGK loci were found to be significant (P = 0.05, P = 0.005, P = 0.05, respectively, not allowing for multiple tests).     

Familial dyslexia: use of genetic linkage data to define subtypes

Specific reading disability is an example of a complex behavioral disorder which is clinically heterogeneous. It is probably also heterogeneous at the levels of etiology and process (pathogenesis), but there may not be a 1:1:1 mapping of etiology to process to clinical outcome. Thus, classification of cases by clinical features may not lead to discovery of the underlying processes or etiologies, and it may be profitable to define subgroups by etiology. There is evidence for genetic etiology in some cases, but there is genetic heterogeneity as well. Possible genetic models for specific reading disability include polygenic, oligogenic, and single gene inheritance, and there are several types of genetic analysis that can be used to determine which of these modes of inheritance may be present. Identification of individual genes is possible in single gene and oligogenic disorders. Clinical studies and molecular analysis can then be used to determine gene function.     

Intravenous chlorimipramine and depressive subtypes.

An open clinical trial with intravenous chlorimipramine was carried out on twenty depressed inpatients, diagnosed as primary or secondary affective disorders following a classificatory scheme for use in psychiatric research. Eleven of twelve patients with primary affective disorders had a significant decrease in symptoms of depression at the end of two weeks. In contrast, eight patients with secondary affective disorders did not show such significant improvement. Changes in physiological parameters (systolic blood pressure) were significantly greater in the primary affective disorders than in the secondary ones. It is inferred from the results of this trial, that intravenous administration of chlorimipramine is a safe and feasible procedure, which may compare to electroconvulsive therapy in the treatment of severe unipolar and bipolar depressions.     

Familial Alzheimer's disease. Evidences for clinical and genetic heterogeneity.

We report the genealogical, clinical and molecular genetic findings of a new family with autosomal dominant early-onset Alzheimer's disease (FAD) discovered in Torino (Italy). Up to now, the pedigree comprises 1500 members, distributed in 8 generations. 22 patients affected with Alzheimer's disease have been identified. The clinical course of the disease was fairly uniform in all the patients. An high incidence of myoclonic jerks and epileptic seizures was found. Molecular genetic studies showed the presence of positive but nonsignificant lod scores between chromosome 21 anonymous DNA markers and the disease. The data obtained from the Torino family were computed together with those of additional 47 pedigrees, with both early-onset and late-onset Alzheimer's disease. A predisposing locus for the disease was found on the pericentromeric region of chromosome 21 only in early-onset FAD pedigrees.     

Depression spectrum disease versus pure depressive disease. Clinical, personality, and course differences

In a group of 191 women admitted to the University of Iowa Psychiatric Hospital for depression over a 45-year period and selected on the basis of alcoholism or antisocial personality, vs. depression, in a parent, 105 probands fit into the depression spectrum group (parental alcoholism or antisocial personality) and 86 into the pure depression group (parental depression). Few differences were found between the presenting clinical pictures (including precipitating factors) of the two groups; but depression spectrum patients and pure depressive patients showed study differences in the areas of personal problems and personality as well as course of illness. The depression spectrum patients were significantly less likely to have loss of interest in usual activities as a symptom at index admission. They were significantly more likely to have had a history of sexual problems, to have been divorced or separated before, to have been described as irritable, and to report having previously been depressed. They are nonetheless significantly more likely to recover completely and have no relapse of depression. The pure depression group were significantly more likely to have depressed sisters, and suicide was much more frequent in their ill parents. Thus, important personality and course differences separate depressive spectrum disease from pure depressive disease;     

Familial unipolar depressive illness: a pedigree study.

The author reports a study of five generations of a family in which several members had unipolar depression responsive to tricyclic medication. He concludes that genetic factors play an important role in this disorder and emphasizes the need for pharmacogenetic studies in psychiatry.     

Familial Creutzfeldt-Jakob disease.

A Finnish family is described with 9 cases of presenile dementia in 3 generations. The mean age at onset was 52 years (range 46--62 years). Progressive dementia, upper motor neuron signs, muscular rigidity, and twitching, irregular tremors were consistent features in the 6 clinically investigated patients and were associated with spongiform change in the cerebral cortex of one autopsy and two brain biopsy cases. The EEG showed progressive slowing without the occurrence of repetitive high-voltage complexes at any stage of the disease. The average duration of the disease (21 months, range 11--36 months) was longer than in the sporadic form of CJD. The occurrence of CJD within this family follows a pattern consistent with an autosomal dominant mode of inheritance, suggesting the possibility of vertical transmission of the presumptive causative agent for example by genomic integration or transplacental passage. However, the occurrence of the disease only through the paternal line of relationships and the presence of a discordant twin pair argue strongly against transplacental passage or transmission via mother's milk. Simple contact infection also seems unlikely, as conjugal cases were not found among the 7 married patients. The interval between the death of the last affected member in generation IV and the time of onset of the disease in the first affected member of generation V was 10 years. Thus setting a minimum incubation period if case-to-case transmission were occurring. To evaluate the role of a genetically determined susceptibility to infection studies on the HLA antigens and other genetic markers are in progress.     

Schizoaffective psychosis. II. Manic, bipolar, and depressive subtypes

Three schizoaffective subtypes-manic, bipolar, and depressive-were compared across multiple baseline (demographic, premorbid, morbid) and long-term outcome dimensions. Though the subtypes were comparable at baseline, the patients with depressive schizoaffective disorder scored consistently better at follow-up, although none of these differences was statistically significant. Results failed to support the validity of such subtyping in schizoaffective disorder, at least in predominantly chronic populations.     

Memory self-appraisal and depressive symptoms in people at genetic risk for Alzheimer's disease.

OBJECTIVES: A previous study found that subjective memory loss in middle-aged and older persons is associated with the major genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele. No previous study has focused on subjective memory complaints and depressive symptoms in the same subject population at genetic risk for Alzheimer's disease. METHOD: Sixty-six persons (mean age = 64 years, range = 43 to 82 years) without major depression or dementia but with mild age-related memory complaints were rated for severity of depressive symptoms, using the Hamilton Depression Rating Scale, and assessed for the presence of the APOE-4 allele. Severity of subjective memory loss was assessed using the Memory Functioning Questionnaire, which measures four memory domains: frequency of forgetting, seriousness of forgetting, retrospective functioning, and mnemonics usage. RESULTS: Depressive symptoms were significantly associated with subjective memory loss in subjects without the APOE-4 allele, for retrospective functioning (perceived change in memory) and mnemonics usage, but not in APOE-4 carriers. The same significant associations were found when the analysis was limited to the 44 subjects in the mid-age range (55-74 years), wherein APOE-4 confers its greatest effects on risk for Alzheimer's disease. CONCLUSION: These results confirm that mild depressive symptoms are related to subjective memory loss, but for some forms of memory complaint, the relationship holds true only for people without the major known genetic risk for Alzheimer's disease.     

The potential relationship between levels of perceived stress and subtypes of major depressive disorder (MDD)

OBJECTIVE: We wanted to explore whether major depressive disorder (MDD) subtypes (melancholic depression, atypical depression, double depression, and MDD with anger attacks) were related to levels of perceived stress, as measured by the Perceived Stress Scale (PSS). METHOD: Our sample [n = 298; female = 163 (55%); mean age 40.1 +/- 10.5 years] consisted of out-patients with MDD. The Structured Clinical Interview for DSM-III-R, the 17-item Hamilton Rating Scale for Depression, the Anger Attack Questionnaire, and the PSS were administered prior to initiating treatment. RESULTS: Depressed women had significantly higher levels of perceived stress (P = 0.02) than depressed men. Greater severity of depression at baseline was significantly related to higher levels of perceived stress (P < 0.0001). After adjusting for age, gender, and severity of depression at baseline, higher levels of perceived stress were significantly related to the presence of anger attacks (P < 0.0001; t = -4.103) as well as to atypical depression (P = 0.0013; t = 3.26). CONCLUSION: Out-patients with MDD who are more irritable and/or present with atypical features have higher levels of perceived stress, indicating a potential reactive component to their depression.     

Familial Parkinson's disease: clinical and genetic analysis of four Basque families

During the last few years several loci have been linked to Mendelian forms of Parkinson's disease (PD). To date, 5 causative genes of 10 identified loci are known, and they have provided enormous insight into the molecular pathways involved in this common neurodegenerative disorder. One of the recently identified loci, PARK8, causes autosomal dominant PD with, apparently, various degrees of abnormal deposition of alpha-synuclein or tau in the neuronal cells in the pedigrees currently reported. We genetically characterized four Basque families and found evidence for linkage of autosomal dominant PD to the PARK8 locus, with a maximum 2-point logarithm of odds score of 3.21 (theta = 0.00) for marker D12S345. The clinical features of these families are those of typical PD, including good response to levodopa therapy, rigidity, and akinesia, and a mean age of 55 years at disease onset.     

Impact of human immunodeficiency virus (HIV) subtypes on HIV-associated neurological disease

Among the many variables affecting transmission and pathogenesis of the human immunodeficiency virus type 1(HIV-1), the effects of HIV subtypes, or clades, on disease progression remain unclear. Although debated, some studies have found that the variable env and pol sequences of different subtypes of HIV-1 may endow some subtypes with greater degrees of cell tropism, virulence, and drug resistance, which may lead to differences in overall disease progression. HIV-associated dementia (HAD) appears to be associated with viral diversity and markers of immune activation. Africa has the highest prevalence of HIV, largest viral diversity, and is where clade recombination occurs most frequently. All of these factors would suggest that HAD would pose the largest threat in this region of the world. Although investigations into the effects of different subtypes on overall disease progression are well documented, few have looked into the effects of subtypes on neurological disease progression. This review highlights the need for more international research involving the neurological effects and especially the clinical presentation of dementia for the entire range of the group M HIV-1 subtypes.     

Dysthymic disorder: psychopathology of proposed chronic depressive subtypes

The author develops a nosologic framework for understanding the psychopathology of low-grade chronic depressions: 1) late-onset primary depressions with residual chronicity, 2) chronic secondary dysphorias, having a variable onset age and considered part of the symptomatic picture of nonaffective "neurotic" disorders or reactions to longstanding incapacitating medical diseases, and 3) early-onset characterologic depressions, which include a) character-spectrum disorders developing in the setting of tempestuous early object relationships and b) subaffective dysthymic disorders, conceptualized as genetically attenuated forms of primary affective illnesses. Differences in family history, REM latency, and pharmacologic responsiveness are presented in support of these distinctions. The author also proposes operational criteria to identify a thymoleptic-responsive subaffective dysthymic group.