Nocturnal serum thyrotropin (TSH) surge and the TSH response to TSH-releasing hormone: dissociated behavior in untreated depressives.

TSH secretion, with particular regard to the nocturnal surge of the hormone, was evaluated in 15 women (age range, 35-66 yr; mean, 50 yr) with untreated major endogenous depression and 15 healthy women (age range, 32-67 yr; mean, 53 yr) using an ultrasensitive assay. Mean morning (0830 h) TSH values did not differ in the 2 groups (1.3 +/- 02 mU/L in depressives and 1.4 +/- 0.1 mU/L in controls), whereas mean nighttime (2400-0200 h) values were significantly reduced in depressives (1.5 +/- 0.3 vs. 3.1 +/- 0.3 mU/L; P less than 0.0005). At variance with the control group, morning and nighttime TSH values did not differ in the depressives. The nocturnal serum TSH surge was abolished in 14 of 15 depressed patients. The mean peak TSH value after TRH was slightly yet significantly lower in the depressives. Patients with subnormal (less than 0.4 mU/L) TSH values in the morning had a serum TSH increase after TRH less than 2 mU/L in 5 of 6 cases and a lack of the nocturnal TSH surge in 6 of 6. Among the 9 patients with normal TSH values in the morning, the nocturnal serum TSH surge was lost in 8 of 9, whereas the response to TRH was normal in all. The depressives, at variance with other reports, showed significantly lower values of total and free thyroid hormones. Mean serum sex hormone-binding globulin (SHBG) and ferritin were also significantly reduced. In conclusion, major endogenous depression is associated with a major impairment of TSH secretion, which baseline TSH measurements in the morning and the evaluation of the TSH response to TRH may not reveal. In this regard, the loss of the nocturnal serum TSH rise would appear to be a more sensitive indicator of hypothalamus-pituitary-thyroid axis alterations in depressives than the TRH test, which is commonly used in the evaluation of these patients. The lack of the nocturnal TSH surge may be responsible for the reduced thyroid hormone secretion and supports the case for some degree of central hypothyroidism in endogenous depression.

The comparative efficacy and safety of carbamazepine versus lithium: a randomized, double-blind 3-year trial in 83 patients.

The comparative usefulness of carbamazepine and lithium carbonate in the acute and prophylactic management of DSM-III diagnosed major affective, schizoaffective, or schizophreniform psychoses was investigated in a 3-year, prospective double-blind randomized trial with 83 in- and outpatients. The incidence of side effects was similar in both treatment groups, and side effects generally responded well to dosage reduction. Both drugs were effective in two thirds of the patients and appeared about equal in most outcome measures, except for a significantly higher dropout rate for patients with mood-incongruent psychotic features who were assigned to the lithium group. Both drugs appeared more effective in preventing excited rather than depressive symptoms.

Regional distribution of diazepam and its metabolites in the brain of cat after chronic treatment.

Repeated administration of diazepam leads to remarkable accumulation of N-desmethyldiazepam in white matter structures and in subcortical areas such as thalamus, hypothalamus, and hypophysis. Diazepam and the hydroxylated metabolites were present in lesser amounts. The distribution pattern of diazepam and N-desmethyldiazepam offers a rationale for its efficacy in inhibiting seizures spreading and for the lack of effect on primary foci discharges.

Kinetics of distribution of amphetamine in cats.

The distribution and metabolic fate of amphetamine were studied in cats. In the brain, high levels of drug were detected in the grey matter structures at short intervals after administration, while at longer intervals distribution between white and grey matter areas was more uniform. In peripheral tissues the greatest concentration of the drug was seen in the highly vascularized organs. Para-hydroxy-amphetamine was found in minimal amounts in the liver and kidneys and only at trace quantities in the brain.

Renal tolerance of rubidium chloride: short-term clinical evaluation.

The rubidium and lithium ions are known to have opposite effects on a wide range of biochemical and behavioral parameters in experimental animals. Based on the proven effectiveness of lithium as an antimanic agent, several trials have been conducted with rubidium in the acute treatment of the depressive phase of bipolar illness. The results to date are promising. However, the 30- to 60-day biologic half-life of rubidium has mandated careful studies of potential toxicity before engaging in long-term administration of this ion to depressive subjects. One area of potential concern is the possibility of renal toxicity, which could be expressed as unexpectedly increased retention of rubidium. The data in this paper show that after 15 days of rubidium administration, there are no changes beyond the normal range in a variety of kidney function tests, including in four enzymes which are specific markers of tubule cell function.

A prospective study of stability and change over 2 years of affective temperaments in 14-18 year-old Italian high school students.

OBJECTIVE: It is generally accepted that temperament is not entirely stable, and that it changes with development, particularly in juvenile subjects; also, some temperaments are believed to be inherently more unstable. There is a great deal of current interest in Kraepelin's thesis that temperamental dysregulation in juvenile subjects represents the constitutional foundation from which the more florid episodes of manic-depressive illness arise; the cyclothymic, hyperthymic, depressive and irritable temperaments under consideration might represent the first observable phenotypes of the genetic diathesis for bipolarity. The analyses on the temperamental attributes in juvenile subjects were undertaken within this theoretical framework. METHOD: We evaluated 206 Italian high school students (14-18 years old) by means of a semi-structured affective temperament interview (TEMPS-I) at T0 and T1 two years later. Age, sex and psychometric properties of TEMPS-I raw scale score and weighted cut-off (as specially weighted linear combination of items) were used as predictive variables of stability. RESULTS: Affective temperaments had a low to moderate level of stability, reaching 60% in the case of subjects with dominant cyclothymic temperament. The stability of the depressive temperament was primarily related to its weighted cut-off. The stability of the hyperthymic temperament appeared related to male sex, young age, and total scale score. Male sex represented the best stability predictor for the cyclothymic temperament as well. The group of subjects with an unstable depressive temperament showed a change toward the dominant cyclothymic temperament, whereas individuals with unstable hyperthymic temperamental traits moved on towards the dominant cyclothymic and depressive temperaments. The irritable construct was the least stable. LIMITATIONS: The infeasibility of a multiwave design represents the main limitation in evaluating the predictors of stability. Furthermore, in the present analyses, the size of the cyclothymic subsample was small. CONCLUSION: Our data indicate considerable fluctuation and instability in depressive and hyperthymic temperaments in mid-adolescence. The cyclothymic temperament appears to be the most stable. Interestingly, cyclothymic moodiness appears more persistent in juvenile males; likewise persistent hyperthymic traits appear more of a "male" attribute. CLINICAL AND PUBLIC HEALTH IMPLICATIONS: We submit that these sex-relevant traits could be important in the risk of developing juvenile bipolarity. Literature review indicates that clinical studies, albeit on small samples, have already provided some support for this thesis. Larger studies on epidemiological samples could be more informative from a public health perspective. A user-friendly affective temperament questionnaire, which is under development, is critical for the methodology of such studies. Our study indicates that the present version of the Akiskal-Malya questionnaire can be easily used post-pubertally. Age adjustment must be considered for younger subjects.

Current issues in the identification and management of bipolar spectrum disorders in 'special populations'.

Bipolar disorder is a common, lifelong condition that can present during childhood, adolescence, adulthood or later in life. It may occur alone but, more frequently, is complicated by comorbid psychiatric and medical disorders. As such, bipolar disorder presents in many different special populations, each of which warrants specific considerations of diagnosis, treatment and management. This review summarizes common issues concerning recognition of bipolar disorder, particularly in younger patients, discusses the prevalence and treatment of anxious disorder and addictive comorbidity, and considers bipolar disorder in the institutionalized and forensic populations. Treatment options and the supporting evidence are discussed.

The semi-structured affective temperament interview (TEMPS-I). Reliability and psychometric properties in 1010 14-26-year old students.

BACKGROUND: The purpose of this study was to evaluate the reliability and psychometric properties of the Semistructured Affective Temperament Interview, and determine cut-offs for each temperament. METHOD: 1010 Italian students aged between 14 and 26 were evaluated by means of the Akiskal and Mallya criteria in a Semistructured Interview for depressive, cyclothymic, hyperthymic, and irritable temperaments. RESULTS: This instrument has very good reliability and internal consistency. The percentage of subjects with a z-score higher than the second positive standard deviation ( + 2 SD) on the scales of depressive and cyclothymic temperaments are 3.6% and 6.3% (reaching scores of 7/7 and 9/10), respectively. Hyperthymic traits, on the other hand, are widespread in our sample: most subjects are included within the second positive standard deviation ( + 2 SD), and 8.2% of these reach a 7/7 score; therefore, the problem of defining a cut-off for this temperament is still open. By contrast, the irritable temperament is rare, conforming to a non-gaussian distribution, with 2.2% of cases above the second positive standard deviation ( + 2 SD). LIMITATION: The data are based on subject report without collateral information and external validation. CONCLUSION: This study contributes to more accurate definition of cut-offs for individual temperament scales. The standardization of the interview thus makes it possible to compare three out of four temperamental scales, showing the dominant temperamental characteristics for each subject. Prospective studies are needed to demonstrate the stability of these traits over time.

TEMPS-I: delineating the most discriminant traits of the cyclothymic, depressive, hyperthymic and irritable temperaments in a nonpatient population.

BACKGROUND: Although most personality constructs have been standardized in population studies, cyclothymic, depressive, irritable and hyperthymic temperaments putatively linked to mood disorders have been classically derived from clinical observations. METHODS: We therefore administered the semi-structured affective temperament schedule of Memphis, Pisa, Paris and San Diego, Interview version (TEMPS-I) -- in its original University of Tennessee operationalization -- to 1010 Italian students aged between 14 and 26. The interview, administered in a randomized format, took 20 min per subject. RESULTS: The semi-structured interview was easy to administer and well accepted by subjects, with no refusals. Principal component analysis with varimax rotation confirmed the hypothesized four-dimensional factor structure of the interview, with good to excellent internal consistency. Furthermore, discriminant analysis and multiple regression provided suggestions for identifying the traits that are most useful in defining a weighted cut-off for each of the temperaments (and which, with minor exceptions, are in agreement with those previously proposed on clinical grounds). In an additional exploratory factorial analysis, a depressive type which loads negatively on hyperthymia was distinguished from cyclothymia; the irritable temperament did not appear to have significant loading on either factor. LIMITATION: All the present analyses were internal to the scale itself, but ongoing studies are comparing them with other systems of temperament as well as testing their clinical cogency for affectively ill populations. CONCLUSION: While more work needs to be done on better operationalization of the irritable temperament, our findings overall support the existence -- in a relatively young nonpatient population -- of cyclothymic, depressive and hyperthymic types according to the classic descriptions of Kraepelin, Kretschmer and Schneider, in their TEMPS-I operationalization. CLINICAL IMPLICATIONS: Coupled with a previous report identifying 10% of the same 14-26-year-old nonpatient population meeting an empirically defined statistical cut-off for these temperaments, the present data define the putative 'fundamental states' that Kraepelin considered to be the personal predisposing anlagé of major affective disorders.

Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome, neuropharmacological considerations, and new therapeutic vistas.

Dysthymia, as defined in the American Psychiatric Association and International Classification of Mental Disorders, refers to a prevalent form of subthreshold depressive pathology with gloominess, anhedonia, low drive and energy, low self-esteem and pessimistic outlook. Although comorbidity with panic, social phobic, and alcohol use disorders has been described, the most significant association is with major depressive episodes. Family history is loaded with affective, including bipolar, disorders. The latter finding explains why dysthymia, especially when onset is in childhood, can lead to hypomanic switches, both spontaneously and upon pharmacologic challenge in as many as 30%. Indeed, antidepressants from different classes -tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase A (RIMAs), selective serotonin-reuptake inhibitors (SSRIs) and, more recently, amisulpride, and spanning noradrenergic, serotonergic as well as dopaminergic mechanisms of action - have been shown to be effective against dysthymia in an average of 65% of cases. This is a promising development because social and characterologic disturbances so pervasive in dysthymia often, though not always, recede with continued pharmacotherapy beyond acute treatment. Despite symptomatic overlap of dysthymia with chronic fatigue syndrome - especially with respect to the cluster of symptoms consisting of low drive, lethargy, lassitude and poor concentration - neither the psychopathologic status, nor the pharmacologic response profile of the latter syndrome is presently understood. Chronic fatigue today is where dysthymia was two decades ago. We submit that the basic science - clinical paradigm that has proven so successful in dysthymia could, before too long, crack down the conundrum of chronic fatigue as well. At a more practical level, we raise the possibility that a subgroup within the chronic fatigue group represents a variant of dysthymia.

Involvement of serotonin system in bulimia.

Platelet 3H-imipramine binding was investigated in 8 patients affected by bulimia according to DSM III criteria, and in 7 healthy volunteers. The Bmax +/- SD (fmol/mg protein) was 356 +/- 53 in patients, and 1144 +/- 134 in controls. The Kd +/- SD (nM) was 1.35 +/- 0.44 in patients, and 1.90 +/- 0.72 in controls. There was a significant difference (p less than 0.0001) in Bmax values in the two groups, whereas no significant difference was observed in Kd values. This study suggests the possible involvement of the indoleamine system in bulimia.

Binding of imipramine to platelet membranes is reduced in panic attacks.

The binding of imipramine (IMI) to platelet membranes was investigated in 13 patients suffering from panic attacks (PA), in 5 patients affected by schizophrenic disorder (S), and in 11 healthy volunteers (V). From 6 volunteers, from 5 patients with panic attacks, and from all the schizophrenic patients, blood samples were collected in the spring, whereas from the others the samples were collected in the autumn. IMI binding was studied according to a protocol provided by the WHO. Binding parameters, the maximum binding capacity (Bmax), and the dissociation constant (Kd) were measured after construction of the Scatchard plot. The differences between V and PA and between V and S were tested by analysis of variance followed by a t-test. Overall and intragroup relationships between Bmax or Kd and diagnosis and season were assessed by a 2-way analysis of variance (ANOVA). Bmax (mean +/- SD) was 947 +/- 269 (V), 742 +/- 160 (PA), and 712 +/- 254 (S) fmol/mg protein. V was different from PA (P less than 0.04) and from S (P less than 0.01). Kd (mean +/- SD) was 1.41 +/- 0.6 (V), 1.15 +/- 0.6 (PA), and 0.79 +/- 0.20 (S) nM. V was different from S only (P less than 0.01). Our results show that panic attacks and schizophrenia decrease the binding capacity of IMI in platelets. In addition, we found a significant difference between patients and controls only for the samples taken in the spring. No statistically significant difference was detectable between the 2 groups in the autumn samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of specificity of reduced platelet imipramine binding in different psychiatric conditions.

We compared 3H-imipramine binding in 10 major depressives with that in 29 healthy volunteers, 13 patients with panic disorder, 9 patients with bulimia, 9 suicide attempters, and 6 schizophrenic patients. None of the comparison groups had histories of major mood disorders, except the suicide attempters. We found a significant reduction of the maximum binding capacity (Bmax) in all groups of patients as compared with healthy controls. These data cast doubt upon the specificity of the decrease of platelet 3H-imipramine binding in major depression, but suggest a possible pharmacological common denominator involving the serotonin system.

High-affinity 3H-imipramine binding sites: a possible state-dependent marker for major depression.

Ten patients with DSM-III diagnoses of nonbipolar recurrent major depression were studied in an attempt to assess the relationship between 3H-imipramine binding site density and clinical depressive state. They were compared with eight healthy controls who had no past or family history of affective disorders. Evaluations with the Hamilton Rating Scale for Depression and the Self-Rated Scale for Depression were done on the same day as platelet collection at baseline, and also at 2 and 5 weeks after the beginning of treatment with tricyclic antidepressants. The number (Bmax) and the affinity (Kd) of platelet 3H-imipramine binding sites were highly correlated with the improvement of the clinical depression. These results raise the interesting possibility that a decrease in 3H-imipramine binding sites may be a state-dependent marker in patients suffering from nonbipolar recurrent major depression.

Evaluation of thyroid function in patients with rapid-cycling and non-rapid-cycling bipolar disorder.

The problem of whether rapid-cycling (RC) bipolar disorder is more frequently associated than non-rapid-cycling (NRC) bipolar disorders with thyroid dysfunction was investigated in two groups of 11 women matched for age and therapy. Seven patients in each group were under chronic lithium therapy. Both RC and NRC patients, as compared to euthyroid controls, showed a reduction in mean total and free thyroid hormone concentrations, subnormal values of free thyroxine being found in four RC and three NRC patients. No patient had supranormal baseline thyroid stimulating hormone (TSH) values, but an exaggerated TSH response to thyrotropin releasing hormone was found in three RC and two NRC patients: all these patients had been receiving lithium therapy for more than one year. No differences in the prevalence of goiter and thyroid-directed autoantibodies were observed in the two groups. These data confirm that bipolar disorder, especially during treatment with lithium, is associated with at least subclinical hypothyroidism, and suggest that RC patients do not differ from NRC patients in the prevalence of spontaneous or lithium-induced thyroid hypofunction. Lithium-induced hypothyroidism is likely to be related to the length of treatment.

Pharmacokinetics of pinazepam in healthy volunteers.

The kinetics of pinazepam were studied in six healthy male volunteers aged between 26 and 31 years. The drug was administered in a single oral dose (10 mg). The concentrations of the parent compound and metabolites were measured in the plasma and urine by gas-chromatographic analysis. Plasma levels of pinazepam were fitted to a two-compartment open model with first order absorption rate using a three-exponential equation. Absorption rate constant and peak plasma levels of pinazepam were 1.36 +/- 0.15 h-1 and 36.8 +/- 5.1 ng/ml respectively. Plasma decay of the drug consisted of an initial rapid elimination phase (alpha = 0.46 +/- 0.06 h-1) followed by a slow one (beta = 0.046 +/- 0.004 h-1). N-desmethyldiazepam was the only metabolite detected in the plasma. Its plasma concentrations were higher than those of the parent compound shortly after administration. Urine was collected for 72 h after dosing. Those specimens contained unconjugate pinazepam and N-desmethyldiazepam and glucuronated oxazepam and 3-OH-pinazepam. Only 0.016% of the pinazepam administered was recovered as unchanged compound in the urine.

Imipramine receptors in human platelets: effect of age.

Imipramine receptors were studied in platelets from six healthy young subjects (age between 24 and 38 years), five newborns, and six healthy elderly persons (age between 70 and 81 years). Binding parameters, the maximum binding capacity (Bmax) and the apparent dissociation constant (Kd), were determined by Scatchard's analysis. Level of differences between young subjects and the other groups was determined by Student's t-test. Bmax (mean +/- SD) was 1162 +/- 138 (young persons), 564 +/- 65 (newborn), and 508 +/- 98 (elderly persons) fmol/mg protein. The figure for the young was different from that of the newborn (p less than 0.001) and the elderly (p less than 0.01). Kd (means +/- SD) was 1.78 +/- .69 (young persons), 0.68 +/- 0.13 (newborn), and 0.80 +/- 0.27 nM in the elderly. Kd in the volunteers was different from that in the newborn or the elderly subjects (p less than 0.01). Imipramine receptors in platelets appear to be influenced by development and aging.

Use of carbamazepine in acute psychosis: a controlled study.

A randomized double-blind study was performed to compare the therapeutic effects of lithium and carbamazepine (CBZ) each administered in combination with chlorpromazine (CPZ) for 3 weeks in women with acute psychosis. Thirty patients were studied. The initial dose was 1200 mg/day for CBZ and 900 mg/day for lithium, and it was subsequently modified according to plasma levels and clinical indications. The dose of CPZ was free and depended on the severity of symptomatology. Both treatments produced a significant improvement in psychotic symptoms without significant differences between the treatment groups. Also, as regards tolerability no clinically relevant differences were found between the two groups. During the first week of treatment the CPZ dose required in the CBZ group was significantly lower than that administered to the lithium group, indicating that CBZ had a greater sedative action; however, this difference decreased as treatment continued. These results confirm that CBZ is a valid alternative to lithium in the treatment of acute psychosis.

[Lithium and the kidney. Acute effects on ADH secretion and enzymuria]. / Rene e litio. Effetti acuti sulla secrezione di ADH ed enzimuria.

The short-term (30 days) effects of lithium carbonate on ADH secretion, urinary enzyme secretion (specific markers of tubular damage), fractional excretion of sodium, calcaemia, calciuria and fractional reabsorption of phosphate, plasma and urinary Ca, urea and creatinine clearance were assessed in 15 female patients with emotional disorders. An immediate increase in diuresis was noted. At least in the acute initial phase, this phenomenon appears to be caused by inhibited ADH incretion. No significant variation were noted in calciuria or the fraction of sodium secretion but there was a significant increase of enzymuria, confirming the potential nephrotoxicity of lithium treatment.

Distribution of inhaled mercury (203Hg) in various organs.

Mercury and its derivatives have long been known to be toxic for the brain and other organs in both animals and man. The distribution of inhaled radioactive mercury (203Hg) in body tissues of rats and mice was investigated by means of a micro-autoradiographic technique. Animals were exposed to 203Hg vapours 6 h daily for 10 days, and then sacrificed at different times after the last exposure. Whole-body autoradiograms showed significant uptake of labelled mercury by the kidney, brain, myocardium, intestine and liver, in decreasing order. Micro-autoradiography demonstrated selective localization of 203Hg in the cytoplasm and processes of neurons, whereas little radioactivity was found in the glial cells of the gray and white matter. High levels of 203Hg were detected in nuclei of the cerebellum, midbrain, pons and medulla, in the Purkinje cells of the cerebellar cortex, and in the epithelium of the ependyma and choroid plexus. In the lung, radioactivity appeared to be confined to the erythrocytes of small blood vessels, which may be the carriers of this metal to the brain. In the liver, ingested but not inhaled radioactivity was concentrated in the reticulo-endothelium. In the kidney, proximal and distal convoluted tubules, but not the medulla or the glomeruli, took up large amounts of inhaled 203Hg. Mercury is distributed to many organs in addition to the brain. It may be transported by circulating red blood cells and it concentrates in the cytoplasm of parenchymal cells.