Effect of concurrent medical illness on dexamethasone suppression test results in depressed inpatients.

A retrospective evaluation of the clinical records of 138 depressed patients, who received the dexamethasone suppression test (DST) as part of a standardized physical and psychiatric assessment protocol, revealed that 60 had acute, chronic (mild or severe), stable or remitted medical conditions. The proportion of DST nonsuppressors did not differ between depressed subjects with medical conditions (45% nonsuppressors) and those without (34.6% nonsuppressors; p greater than 0.2). However, all of the six subjects with acute or chronic-severe medical conditions were found to be nonsuppressors (p = 0.003). These results may help clarify the medical exclusion criteria for the clinical application of the DST.

Hyperparathyroidism, hypothyroidism, and impaired renal function after 10 to 20 years of lithium treatment.

Of 19 patients who had been receiving a therapeutic dosage of lithium carbonate for 10 to 20 years, 8 (42%) were found to have some laboratory evidence of hyperparathyroidism. Of the 3 who had parathyroid surgery, 2 had hyperplasia and 1 had a solitary adenoma, an unusually high incidence of hyperparathyroidism. Unusual features of lithium-induced hyperparathyroidism in this series include (1) low urinary calcium excretion and the absence of nephrolithiasis, (2) normal urinary cyclic adenosine monophosphate excretion, and (3) normal plasma inorganic phosphate. Eight patients (42%) required treatment for hypothyroidism. Three patients (16%) had impaired kidney function. While these observations do not contraindicate the continued use of lithium carbonate in manic depression, they strongly emphasize the need for close laboratory surveillance.

Toronto-Rochester Depression study of 116 HLA-typed kindreds.

The Toronto-Rochester Depression study consisted of 116 pedigrees ascertained for multiple cases of major affective disorders. Among the 857 psychiatrically evaluated family members, of whom more than 85% were given a structured interview, 363 had major affective disorder by Research Diagnostic Criteria and 385 had no history of psychological aberration. HLA region genes were typed in 804 of these persons.

Analysis of the Toronto-Rochester Depression Study follow-up data confirms an HLA-region gene contribution to susceptibility to affective disorder.

Analysis of HLA haplotype distributions in relation to major affective disorder in affected sibling pairs and affected aunt or uncle and niece or nephew pairs confirmed that HLA-region genes do contribute to susceptibility to affective disorder. The data indicated that this effect may be greater in unipolar than in bipolar disorder, and more apparent in families with few affected members than in heavily loaded families. Nonrandom assortment of HLA haplotypes to affected and unaffected offspring in "low load" families occurred principally for the haplotype transmitted from the side of the family without affective disorder. We conclude that HLA-region genes contribute to but are not the only factor in susceptibility to major depression.

Confirmation of the relationship of HLA (chromosome 6) genes to depression and manic depression. II. The Ontario follow-up and analysis of 117 kindreds.

HLA typing was conducted on 577 family members of 86 families having at least two first-degree family members with a lifetime history of major depression or bipolar disorder. The results were combined with a follow-up study of 10 Newfoundland kindreds and with the data obtained from our previous studies, giving a total cohort of 117 families of diverse ethnic and geographic origin. There was increased sharing of HLA haplotypes, as compared with random expectation, over all possible pairwise comparisons both in the follow-up studies (P less than 0.025) and in the total data (P less than 0.01). The increase in HLA haplotype sharing over random expectation was greater if comparisons within heavily loaded sibships (by prior convention, sibships with three or more affected siblings) were omitted from the analysis (P less than 0.002). There was also non-random transmission of HLA haplotypes in 50 families selected for a low-load, unaffected parent (P less than 0.005). Thus, we conclude that genes in the HLA region of chromosome 6 constitute one of the elements in the multifactorial etiology of affective disorder. This conclusion does not depend on any assumption concerning genetic heterogeneity or epistasis or on specific modes of transmission, penetrance values or linkage distances. In addition, the data suggest that chromosome 6 region genes may have a different effect in unipolar and bipolar illness.

The relationship of HLA to depression and manic depression. I. The Newfoundland follow-up.

This report constitutes the Newfoundland component of a large scale replication study to assess the relationship of HLA to affective disorders; the Ontario component will be published subsequently. In a collaborative study between the University of Toronto, Memorial University and the University of Rochester, first degree family members of Probands with major affective disorder in Newfoundland were assessed for the lifetime presence of psychiatric disorder; their blood was also typed for Human Leucocyte Antigens (HLA). Because of the high rate of refusal to participate, only 10 Newfoundland families could be assessed completely. While this number of families is too small to evaluate the role of HLA as a marker of susceptibility to affective disorder, the results will be added to those of the larger Ontario component. Some problems of conducting research in communities similar to those found in Newfoundland are briefly discussed in the context of characteristics of the Probands in the study group as compared with those of subjects who refused entry into the study.

Evidence for homogeneity of major depression and bipolar affective disorder.

This study compared the morbidity risk for affective disorder in relatives of probands who had bipolar (BP) or major depression (UP). Other risk factors were also evaluated. 112 consecutively admitted inpatients yielded 621 relatives with diagnostic information based on either the Renard diagnostic interview, hospital records or information from at least two reliable relatives using the Feighner diagnostic criteria. Similar age corrected morbid risk estimates were found for family members of UP and BP probands of 0.243 and 0.246. There was a 50% increase in morbidity risk for women in all three generations but no relationship to the diagnosis of the proband. A proportional hazards (life table) analysis demonstrated that probands with onset prior to age 40 had relatives with younger onset and higher risk. None of the analyses, including logistic regression and proportional hazards, differentiated UP from BP illness.

Desipramine and 2-hydroxydesipramine in human breast milk and the nursing infant's serum.

Desipramine and its metabolite 2-hydroxydesipramine were measured in the milk of a nursing mother and in the plasma of the mother and infant during administration of 300 mg/day of desipramine to the mother. Similar concentrations of both compounds were found in maternal plasma and milk. A pharmacokinetic plot of the milk over 24 hours showed the expected rise and fall of the substances following a single nighttime dose. Neither parent compound nor metabolite could be detected in the infant's serum even though the measurements were made shortly after peak ingestion by the infant. Furthermore, no clinical signs of toxicity were observed in the infant after 3 weeks of treating the mother with desipramine.

Neurotransmitter metabolites and endocrine responses in depression.

Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 less than p less than .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.

Elevated 3,4-dihydroxyphenylethyleneglycol (DHPG) excretion in dexamethasone resistant depressed patients.

Urinary and plasma DHPG and MHPG were estimated in patients with MADD and showing DST non-suppression as compared to those with normal suppression. Day and night 12h urine collections and morning plasma samples were analyzed by GC-MS for total MHPG and DHPG and free MHPG levels. Urinary DHPG excretion was significantly elevated in DST non-suppressors compared to suppressors, but no differences were found in urinary MHPG or plasma glycol levels. Elevated DHPG excretion in DST non-suppressors suggests that increased peripheral sympathetic NE activity occurs in association with dexamethasone resistance in MADD.

The use of carbamazepine as an adjunctive medication in the treatment of affective disorders: a clinical report.

This is a report of an open clinical trial of Carbamazepine in the treatment of patients who suffered from affective disorders and who did not have an adequate response to Lithium or other medications. Our findings suggest that Carbamazepine can be a useful adjunctive medication when used in combination with Lithium and other psychotropic medications. The characteristics of the patients who responded were examined. The clinical state of the patients at the point of intervention varied; eight patients were manic and four patients were depressed. Four patients were judged to have had markedly effective responses, four showed an effective response and in four there was a slightly effective response. From the duration of the trials it was evident that in cases where Carbamazepine produced a good response its effect was seen as early as two weeks. The mean daily dose used varied from 300-1300 mgs. Because of the open nature of this trial, Carbamazepine was not withdrawn except in one instance.

The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma.

Plasma levels of desipramine (DMI) and the unconjugated form of its principal metabolite 2-hydroxydesipramine (OH-D) were measured under steady-state conditions in nine depressed inpatients during treatment with 75 mg DMI every 12 hr and after at least 1 wk of an increased dose of DMI (after steady state). When DMI dosage was raised after an initial steady state had been reached, the rise in plasma DMI level was proportionately greater than the increase in dosage, suggesting saturation of DMI elimination pathways. Levels of OH-D rose in proportion to dose, suggesting saturation of DMI elimination by 2-hydroxylation could not explain DMI plasma level changes. In contrast, there were no dose-dependent effects on the disposition of amitriptyline or its metabolite nortriptyline in subjects receiving the same amitriptyline dose.

Genetic counselling: its need in psychiatry and the directions it gives for future research.

The methods for investigating the extent to which genetic factors can influence vulnerability to psychiatric illness are, in increasing order of precision: family, twin, and adoption studies. The evidence from these studies is in support of a gene-environment interaction for schizophrenia and the affective disorders. While the family study method cannot supply precise etiological data, the empirically derived information can be used by the genetic counsellor to provide empirical risk estimates to the counsellee. The psychiatrist, geneticist, and social worker make an appropriate team for reliable genetic counselling. The clinician must determine the precise psychiatric diagnoses in family members which the geneticist may use to estimate risk. The social worker can follow-up the counselling session or sessions to assess the counsellees' understanding of what has been told to them. It is stressed that while genetic counselling should be available, clinical judgement should be exercised to ensure its appropriate use.

The occurrence of secondary affective disorder in an in-patient population with severe and recurrent affective disorder.

One hundred and eighty nine consecutive in-patients with treatment-resistant affective disorder were administered the Renard Diagnostic Interview to determine whether the 45 with secondary affective disorder (SAD) differed from the 144 with primary affective disorder (PAD). The SAD group, including 15 subjects with bipolar disorder, had an earlier mean age of onset of depression and contained more unmarried individuals. The total secondary group could not usefully be differentiated by assessment of clinical symptoms or discriminating analysis of social and clinical variables. While the present study of a severely depressed population does not lend itself to generalisability, this combined sample does have characteristics of patients used in biological investigations. No significant inter-group discrimination was found to support a previous assumption that identification of a prior psychiatric disorder provides the most suitable mechanism for selecting a population for research in affective disorders.

Seasonal variation in platelet 3H-imipramine binding: comparable values in control and depressed populations.

Recent findings of reduced 3H-imipramine binding in platelets of depressed patients compared to healthy controls have been proposed as a biological marker of depression. However, these studies failed to consider the possible occurrence of seasonal variation in the binding characteristics. Our results show a highly significant seasonal variation in platelet 3H-imipramine binding which occurs in both normal and depressed populations. Furthermore, when annual rhythms are taken into account, there is no difference in the binding parameters in the two populations.

Life events precipitating mania.

A study of 20 manic patients, with patient and matched control comparisons, showed a two fold increase in life events during the 4 month period before admission to hospital. Life events, independent of affective illness and having significant objective negative impact (i.e. traumatic) were significantly more common. These findings are considered in relation to social relationships, family history of affective illness and the use of psychotropic medication.

Treatment of intractable rapid-cycling manic-depressive disorder with levothyroxine. Clinical observations.

Hypermetabolic doses of levothyroxine sodium produced remissions in five of seven women with intractable manic-depressive illness who were followed up for nine months to nine years. These patients had previously required long-term or frequent psychiatric hospitalization. The onset of illness was during the postpartum or involutional period and soon developed into cycles of four or more episodes yearly that did not respond to therapy with lithium carbonate, antidepressants, or neuroleptics. The levothyroxine treatment was unsuccessful in two men and one adolescent girl.

Depressive disorders and HLA: a gene on chromosome 6 that can affect behavior.

To determine whether HLA-linked genes on chromosome 6 influence susceptibility to depressive disorders, we tested hypotheses concerning the distribution of HLA haplotypes among specific constellations of affected and unaffected family members. HLA haplotype identity among pairs of affected siblings in families with two affected siblings and among pairs of older unaffected siblings in families with one or two affected siblings was increased over random expectation (P less than 0.005). There was no increase in HLA haplotype identity among affected siblings in sibships with more than two affected members. When parents had a relative difference in estimated load of genes for susceptibility, HLA haplotypes were randomly transmitted to unaffected or affected children from the affected, "high-load" parent, but not from the unaffected, "low-load" parent (P less than 0.001). These results locate a gene contributing to susceptibility to depressive illness on chromosome 6 and provide a second example of the value of the hypotheses in defining the genetic bases of nonmendelian, familial diseases.

Controlled exercise elevates plasma but not urinary MHPG and VMA.

The effect of controlled exercise on plasma and urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and vanillylmandelic acid (VMA) was investigated in normal subjects. After 3 days of bed rest, six normal volunteers engaged in controlled exercise adjusted to a constant 40% of the individual's maximum oxygen intake. The exercise program consisted of 4 miles of walking and a half-hour each of bicycle ergometry and treadmill walking. Both plasma VMA and MHPG were higher on the exercise day than on the resting day, while urinary VMA and MHPG levels did not differ from rest to exercise. The mean urinary MHPG/VMA ratio (0.46) differed markedly from the mean plasma MHPG/VMA ratio (2.3). Plasma and urinary MHPG apparently represent different indices of norepinephrine metabolism.

A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania.

Previous investigations of the treatment of mania have resulted in uncertainty about the efficacy of lithium versus a neuroleptic. In addition there have been reports of toxicity with a haloperidol--lithium combination. In order to determine the comparative efficacy of lithium vs haloperidol vs a combination of haloperidol--lithium, we studied 21 severely ill manic patients who all met rigorous criteria for bipolar illness and who required in hospital treatment. Subjects were randomly assigned to 3 groups: (A) Lithium plus placebo (B) Placebo plus haloperidol and (C) Lithium plus haloperidol. The study was conducted in double blind fashion for 3 weeks with the dosages of the medications varied according to clinical response or untoward effects. Subjects on haloperidol and placebo or the haloperidol--lithium combination were significantly improved after 7 days in comparison to the lithium-treated group. Groups B and C did not differ from each other, either in degree of improvement or in side effects. Inspite of the relatively small sample size the results suggest (1) that haloperidol is superior to lithium for treating severely ill acute mania and (2) that while a haloperidol--lithium combination does not result in a significant increase in side effects, it is not superior to haloperidol alone.