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Eighteen families informative for c-Harvey-ras-1 and INS DNA markers were tested for linkage to unipolar depression and alcoholism. No evidence of linkage was found between these DNA markers and the disorders observed in the families. This study fails to replicate the Old Order Amish Study and suggests that a significant degree of genetic heterogeneity may be present among psychiatric disorders.

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.

In evaluating 40 manic-depressive (bipolar) patients who had clinical electroencephalograms, there was a significant relationship between abnormal EEG findings and a negative family history for affective disorder when a comparison was made between patients with various classes of family history.

A neurotic depression is a depression in an emotionally unstable person. Secondary depressions to major personality disorders, neuroses, and drug use disorders fit the above definition. Likewise, primary depressions with a family history of alcohol (depression spectrum disease) are characterized by a long history of stormy life problems and, therefore, would fit the definition. Using these two preexisting characteristics, we examined a group of 401 neurotic depressives and compared them to 536 nonneurotic (endogenous) depressives. The neurotic depressives were younger and the neurotic patients had made more previous suicide attempts. They were less likely to show memory deficits or delusions and less likely to show symptom criteria of melancholia. They were more likely to have suicide thoughts at index. Treatment was more effective in the nonneurotic patients and such patients made fewer suicide attempts in follow-up. These differences confirm the validity of the distinction between neurotic and nonneurotic depression.

Data from the University of Iowa Psychiatric Hospital are consistent with national trends. Inpatients tend to be young, female, and have psychotic rather than non-psychotic disorders. Women were significantly older than men at admission for most psychiatric disorders. During the past 20 years, length of stay has dropped by over 50%, while admissions have almost trebled and re-admissions doubled. Historic trends are reviewed and clinical implications are discussed.

Pituitary-adrenal regulation in healthy subjects and in depressed patients is very dynamic. Interpretation of results of the 1-mg dexamethasone suppression test has usually depended on the result of a single blood cortisol level measurement obtained in the morning or afternoon. We analyzed circulating cortisol concentrations by obtaining blood samples at 20-minute intervals for 24 hours before and after dexamethasone administration in depressed patients. The results illustrate the variability in patterns of escape from the effects of dexamethasone among depressed patients; they also indicate the influence of the sampling time on the test results and thus on the relationship of the test result to various clinical classifications. Finally, these results provide the basis for understanding the consequences of alternative sampling strategies.

Stability of diagnosis in schizophrenia and affective disorders is high. Patients selected according to research criteria for schizophrenia and affective disorders were followed up in a historical prospective study to evaluate their diagnostic stability over a 30- to 40-year period. Our follow-up, lifetime diagnosis, based on blind diagnostic assessment, showed that 92.5% of the personally interviewed schizophrenics were given the follow-up diagnosis of schizophrenia, which was significantly higher than the 78.3% found in affective disorders. However, no significant difference exists when assessment was made on available records of those who died or refused to be interviewed. These stability coefficients are discussed in light of the methodological assumptions involved in a long-term follow-up study. We concluded that the diagnostic stability in schizophrenia and affective disorders were very high and that rigorous diagnostic criteria should be maintained.

The authors looked at the association of illness duration and acute treatment response in 1,087 patients with unipolar major depression. Three treatment groups were compared, including a group that received electroconvulsive therapy (ECT), a group that received antidepressants, and a group receiving neither ECT nor antidepressants. Up to an illness duration of 2 years, treatment was significantly associated with recovery; ECT produced significantly better results than other treatments. However, when the illness had lasted >2 years, the ECT-treated group showed a significant decline in recovery, and ECT was no longer superior to other treatments. We conclude that duration of illness at index hospitalization has an important influence on treatment response rates and the likelihood of recovery by hospital discharge.

We compared the efficacy of electroconvulsive therapy (ECT) and numbers of ECTs received by unipolar depressive (n = 368), bipolar depressive (n = 55), and manic patients (n = 37) in a review of records of patients treated in a 12-year period in a university hospital medical center. Both unipolar and bipolar depressive patients received nine treatments, one half more on average than the number of treatments received by manic patients, but the difference was not significant. ECT was equally effective in unipolar and bipolar depression (69.8 and 69.1%, respectively, rated as "markedly improved"), whereas 78.4% of patients with mania had "marked improvement." Both unilateral and bilateral ECTs were equally effective for the three groups. Bipolar depressive and manic patients receiving mixed courses (some unilateral, some bilateral) received more treatments than did those receiving unilateral or bilateral treatments exclusively and tended not to respond as well. We conclude that ECT is an effective treatment for mania, unipolar, and bipolar depression, that unilateral and bilateral treatments are equally effective, and that no significant difference exists in the number of ECTs used to treat these disorders.

The treatments of 519 depressed patients hospitalized from 1959 to 1969 were compared in a three-year follow-up study with particular reference to mortality. The electroconvulsive therapy (ECT) group had a significantly lower mortality than the inadequate antidepressant treatment group (P less than .05) and the group that received neither ECT nor antidepressants (P less than .025). Although the adequate antidepressant treatment group had a low mortality, statistically significant differences between this and other treatment groups could not be documented. Nonsuicidal deaths (P less than .005), and particularly myocardial infarctions (P less than .01), were significantly more frequent in the inadequately treated group compared to the adequately treated group. The superiority of adequate treatment is especially striking among men and among the older age groups. The results underscore the importance of adequate treatment of depression, especially in the older man.

The risks of various psychiatric illnesses among the first-degree relatives of 160 surgical control patients were estimated. Morbidity risks were calculated separately for males and females because of previous findings showing significant sex differences for certain diagnoses. The findings, based on ICD-9 criteria, demonstrate a significantly higher risk of depression, neurosis, and organic brain syndrome in females than in males. The risk of alcoholism was significantly higher in males.

Genetic linkage was studied in depression spectrum disease, a subgroup of unipolar depressive illness defined by presence of familial alcoholism and/or antisocial personality, using a version of the sib pair method of Penrose. Rigorous research diagnostic criteria were used and the diagnoses were made blind, i.e., without knowledge of the genetic marker results. Possibility of linkage was suggested (p less than 0.005) with the alpha-haptoglobin (alpha-Hp) and third complement component (C3) loci. However, the likelihood that these two markers are not on the same chromosome, and the limitations of the sib pair method, permit these findings to be treated as suggestive only and indicate that these two promising markers should be investigated further, using a more definitive method of linkage detection such as the lod score method.

Onset defined as duration of illness prior to index admission was studied in manic and unipolar depressive patients. The manic patients were far more likely to have an acute onset when defined in this way. Of considerable interest is the fact that depression spectrum disease patients, i.e. those patients with a family history of alcoholism in a first-degree relative, were much less likely than other depressive patients to have an acute onset of their illness. In this case, the acute onset was defined as having occurred within 1 month of hospitalization.

A total of 83 patients receiving diagnoses of major depressive disorder in the pilot phase of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression were used to evaluate two newer methods of classifying depressive disorders on the basis of family history or course. A third subtype based on family history, nonfamilial depression, was compared with the two subtypes originally proposed by Winokur and colleagues, pure depression and depression spectrum diseases. The system for classifying depressions on the basis of course and antecedent disorder, primary vs secondary depression, was also compared. These data from the pilot study indicate that two newer systems for classification have some predictive, construct, and content validity, but both are in need of further investigation before they become accepted methods for the classification of depressive disorders.

The author reviewed data from five studies and found that depressed patients with a history of depression in a parent or child have more sibships containing depression than depressed patients without this family history. Thus, there is a clustering of depressions in certain families. Sporadic pure depressive disease (PDD), where no depressive illness exists in a first-degree family member of a depressed proband, is associated with a later age of onset than familial PDD, where depressive illness does exist in a first-degree relationship. The possibility exists that familial PDD and sporadic PDD are autonomous illnesses. The presence of a family history of depression may be predictive to some extent of a good response to adequate tricyclic medication or ECT.

Considerable evidence suggests that patients with anxiety disorders have secondary depression, and somewhat less evidence suggests that secondary alcoholism is seen in anxiety disorder. Such illnesses as manic-depressive disorder, schizophrenia, and hysteria are likely to be associated with secondary anxiety syndromes. Considerable data support the idea that within families of anxiety disorder patients alcoholism is seen more frequently than would be expected by chance and that within families of alcoholics anxiety disorders are seen more frequently than would be expected by chance. These findings suggest a difference in expressivity for the same familial propensity.

Serum cortisol response to the 1-mg overnight dexamethasone suppression test was studied in 221 depressed patients and 109 nondepressed psychiatric controls. Nonsuppression distinguished patients with primary unipolar depression (65/146) from patients with secondary unipolar depression (0/42) and nondepressed controls (0/109). Furthermore, nonsuppression distinguished the three familial subtypes of primary unipolar depressive illness: familial pure depressive disease (FPDD; 38/50 patients), sporadic depressive disease (SDD; 24/55 patients), and depression spectrum disease (3/41 patients). Moderate elevations in baseline serum cortisol levels were found in FPDD, SDD, and bipolar depression. Medication did not affect the results. The data suggest that the depressive syndrome is composed of separate illnesses, each of which has a distinctive pattern of hypothalamic-pituitary-adrenal axis activity during the depressed state as well as a specific clinical and familial psychiatric history.

The authors studied 401 patients with depressions secondary to psychiatric illnesses (substance abuse disorders or somatoform, anxiety, or personality disorders) or depressions secondary to medical illnesses. They found that the patients with depressions secondary to psychiatric illnesses had an earlier age at onset, were more likely to have suicidal thoughts or to have made suicide attempts, were less likely to have memory problems, were less improved with treatment and more likely to relapse on follow-up, and had more alcoholism in their families than patients with depressions secondary to medical illnesses. Depressions secondary to medical illnesses seem to fit the category of reactive depression, and depressions secondary to psychiatric illnesses fit the definition of neurotic depression.

A classification of chronic psychoses including nonparanoid schizophrenia, paranoid schizophrenia, paranoid state and paranoia (delusional disorder) is presented. This classification is dependent on a systematic increase in number of symptoms with each group. In particular, delusional disorder is examined with regard to family history. It is clear from the data which are presented that delusional disorder is more likely to be associated with a family history of such traits as suspiciousness, jealousy, secretiveness, and the presence of paranoid behavior or delusions. There is evidence that such familial traits are not seen in schizophrenia, only in delusional disorder.

Mortality in a psychiatric population was studied. During the first two years following hospital discharge, natural deaths, accidental deaths, and suicide were excessive. After two years, suicide and accidental deaths continued to be excessive, but not natural deaths. Diagnostic categories were linked to cause-specific deaths. Clinical implications were discussed.

Studies of the underlying components of affective disorders are particularly difficult because of the confounding effects of both genetic and environmental factors. Linkage analysis is a useful tool in delineating the etiology of affective disorders, as it is unlikely that linkage between behavioral traits and blood group polymorphisms could result from environmental effects. The present study used the robust Haseman and Elston sibpair method to analyze linkage between 24 genetic markers and affective disorder in 34 nuclear families from 25 pedigrees (195 people). The probands were ascertained as part of the ongoing NIMH Collaborative Depression Study. Indications of linkage between familial pure depressive disease and MNS and depression spectrum disease and ORM were found, as had been previously suggested. There was also suggestive evidence for linkage between the latter and GC. Results are discussed in terms of methodological differences with previous studies.

Long-term (30-to 40-year) follow-up data for 76 manic patients, 182 depressives. 170 schizophrenics, and 109 controls showed that 10 per cent of the schizophrenics, 8.5 percent of the manics, and 10.6 percent of the depressives who were decreased had died by suicide. None of the controls had committed suicide. The authors suggest that suicide is a significant outcome factor in all three of these illnesses and is likely to occur at an earlier age in schizophrenia than in the other illnesses.

At discharge, a significantly larger percentage of unipolar patients treated with electroconvulsive therapy (ECT) respond with marked improvement as compared with those receiving antidepressants or other treatment. No treatment appears to be more efficacious in the bipolar group. In studying the covariables related to the length of time between hospitalizations, we found that the type of treatment is not important for the unipolar patient, whereas a combination of ECT and antidepressants lengthens the time to rehospitalization of the bipolar patient. Previous hospitalization is an important predictor variable for all patients.

Depression spectrum disease has been defined as an illness in which a first-degree family member has alcoholism and/or antisocial personality. Pure depressive disease may be considered as the remainder of the depressive illnesses or more rigorously as depression in a person who has a family history of depression but no alcoholism. Evidence is presented that the course of the illness is different in the two groups. Depression spectrum disease is more variable, with more personality problems and interpersonal conflict. Preliminary data indicate that depression spectrum disease may be linked to such genetic markers as C3 or alpha-haptoglobin.

The effectiveness of fluoxetine as an antidepressant was contrasted with trazodone in a 6-week double-blind trial in 40 patients. The total score on the Hamilton Rating Scale for Depression and the global improvement score on the Clinical Global Impressions scale favored trazodone at the end of 3 weeks of treatment. However, that difference was no longer apparent during the remainder of the study. The authors hypothesize that fluoxetine 20 mg/day may be an ineffective dosage of the drug or that fluoxetine has a slower onset of antidepressant action than does trazodone.

Mortality data are presented from a two to fourteen year follow-up of 705 primary unipolar depressives, 302 secondary unipolar depressives, and 586 patients with bipolar affective disorder (BAD) hospitalized at a tertiary care facility. Death ascertainment was made through a record-linkage process. Using sex- and age-standardized mortality ratios (SMRs), the mortality experience of the study population was compared with that of Iowa, the geographical area served by the admitting medical facility for this study group. Results show that risk for all-cause mortality was most pronounced during the first two years following hospital discharge, although secondary unipolar depressives continued to show a significant excess of deaths throughout the entire follow-up period. Deaths occurring from natural causes were significantly excessive only during the initial portion of the follow-up. Deaths from unnatural causes were significantly excessive throughout follow-up except for patients with bipolar affective disorder.

Total, differential, and absolute blood cell counts were compared in 66 untreated manics and 178 untreated schizophrenics. Mania was associated with significantly higher total leukocyte counts (p less than .001), accounted for by a significant increase (p less than .0001) in the number of neutrophils. There were no significant differences between the two groups in any other blood cell elements. Using normative values, manic patients had significantly higher frequencies of both leukocytosis (25.8% vs. 12.4%) and neutrophilia (34.8% vs. 12.4%) than the schizophrenic group. These data suggest a significant association between leukocytosis, neutrophilia, and mania.

Our investigation of the pattern of mortality among former inpatients in nine diagnostic groups was based on deaths found among 4,869 former inpatients of the University of Iowa Psychiatric Hospital, Iowa City, during a ten-year period. Comparisons were made with expected values based on a relevant Iowa control population. The first two years of follow-up was a period of great risk but not after. Excessive mortality from "unnatural" causes was found among patients of either sex with an affective disorder, schizophrenia, alcohol or other drug abuse, and personality disorders, among men with acute schizophrenia or neuroses, and among women with depressive neuroses. Women with acute schizophrenia or a psychophysiologic disorder or special symptom were at risk for a "natural" death. These findings confirm the risk of reduced life span that patients in all nine categories share.

The morbidity risk of alcoholism among men in a Midwestern population varied between 5.4 and 7.2%, depending on the criteria used. Among women the morbidity risk was about 0.4%.

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).

All hospital records, interviews, and notes are reviewed on a group of 52 chronic hebephrenic/catatonic schizophrenics who were institutionalized before the era of antipsychotic medications. The authors catalog the presence or absence of individual symptoms of schizophrenia on a year by year basis over a span of 25 years and present this data in a series of bar graphs. Symptoms such as avolition, impaired social interaction, and flat affect become more frequent over the 25 years of follow-up. Hallucinations and delusions become less frequent. Eighteen of the patients are noted to have had a DSM-III personality disorder premorbidly and eight of these are characterized as schizoid personality disorder. Level of insight is found to be poor at the onset of schizophrenia and deteriorates further over the next 5 years. Although the study design contains a sampling bias in favor of chronically institutionalized cases, several lines of evidence suggest that the trends reported here are not artifacts of institutionalization but are due to schizophrenia.

The distribution of leukocytes in the blood stream is affected by levels of circulatory glucocorticoids. Elevated concentrations of cortisol are usually associated with an increase in the number of neutrophils and a decrease in the number of lymphocytes. Since primary depressive illness is often associated with hypercortisolemia, we hypothesized that similar changes in the blood stream of depressive patients may occur. To test this hypothesis, we retrospectively compared leukocyte counts in 177 untreated depressive patients and 178 untreated schizophrenic controls. We found a significant increase in the absolute and relative numbers of neutrophils and a significant decrease in the absolute and relative numbers of lymphocytes in the depressive group. Furthermore, when compared to normative values from the general population, depressed patients showed higher frequencies of both neutrophilia and lymphopenia than the schizophrenic group. These results indicate differences in the regulation of leukocytes in depression and schizophrenia consistent with the effects of higher levels of plasma cortisol in the depressive group.

Using archival data, we conducted a systematic study of consecutive admissions of bipolar patients and found that an early age of onset, a subacute onset, a family history of bipolarity, and the administration of electroconvulsive therapy (ECT) during an index episode were individually associated with a polyepisodic course of illness (three to nine or more episodes) during a period of observation which included onset of illness, index admission, and a period of follow-up. The family history of biopolarity which seems to predispose to multiple episodes suggests that what may be transmitted may not necessarily be a bipolar illness but possibly an illness with many episodes, thus increasing the likelihood of occurrence of a manic episode.

The use of strict criteria for the diagnosis of schizophrenia is quite predictive of a bad prognosis. Should the patient not meet such strict criteria, a family history of remitting illness may be helpful in suggesting a better outcome. In this latter group, the subtype diagnosis of catatonic schizophrenic carries with it a better prognosis.