• The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics.DSM-IIIschizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.

Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine

Objective: The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome. Participants: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments. Conclusions: After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal inci...

The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

https://science.sciencemag.org/content/sci/226/4680/1342.full.pdf

Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

• Positron emission tomography and selective radioligands were used to determine D,and D2dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D,occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1occupancy was 38% to 52%. The D,occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

Positron Emission Tomographic Analysis of Central D1 and D2 Dopamine Receptor Occupancy in Patients Treated With Classical Neuroleptics and Clozapine: Relation to Extrapyramidal Side Effects

• Serum prolactin levels were studied before and during longterm administration of phenothiazines on a twice daily schedule to 27 newly admitted schizophrenic patients. An increase in serum prolactin is believed to be a reflection of inhibition of dopamine receptors in the hypothalamopituitary axis. By 72 hours after the initiation of treatment, all 27 patients had persistently elevated serum prolactin levels averaging 3.2-fold and 3.8-fold in men and women, respectively. There was a lag between clinical response and dopamine blockade, as indicated by serum prolactin levels in most patients. Serum prolactin levels remained elevated during the one- to three-month period subjects were studied, suggesting there was no tolerance to this effect of phenothiazines. Serum prolactin levels tended to be higher with thioridazine than on equivalent doses of chlorpromazine or trifluoperazine hydrochloride. There was some evidence that the magnitude of the serum prolactin elevation correlated with clinical response. After cessation of phenothiazines, serum prolactin levels rapidly reverted to normal within 48 to 96 hours.

The effect of neuroleptics on serum prolactin in schizophrenic patients.

Thyroid function was evaluated in 46 patients with end-stage kidney disease and 42 normal subjects. Patients were studied before and after the institution of maintenance hemodialysis (HD) and after renal transplantation (RT). Serum total triiodothyronine concentrations (TT(3), ng/100 ml, mean+/-SD) were 63+/-17 and 83+/-22 in the non-HD and HD groups, respectively. Values from normal subjects were 128+/-25 and from RT patients 134+/-20. The TT(3) was in the hypothyroid range (<78 ng/100 ml; 2 SD below normal mean) in 80% of non-HD and 43% of HD patients. Mean serum total thyroxine concentration (TT(4)), although within the normal range, was lower than the control value. T(4)-binding globulin capacity was also slightly lower but the difference was not statistically significant. Among patients whose TT(4) was 1 SD below the normal mean, the free T(4) index was equally depressed, suggesting that factors other than decreased binding capacity might be responsible for the low TT(4). In addition, there was a 37% incidence of goiter. Mean serum thyroid-stimulating hormone (TSH) was not elevated and the TSH response to thyrotropin-releasing hormone (TRH) was distinctly blunted, suggesting the possibility of pituitary dysfunction as well. In vivo (125)I-l-T(4) and (131)I-l-T(3) kinetics during 0.2 mg/day of l-T(4) replacement showed marked reduction in T(3) turnover rate in the uremic patients, both before and during HD; the values (mug T(3)/day, mean+/-SD) for the different groups were as follows: normal, 33.8+/-6.1; non-HD, 13.5+/-2.6; HD, 12.9+/-3.1; and RT, 30.3+/-7.1. The low T(3) turnover rate was due to impaired extrathyroidal conversion of T(4) to T(3). The mean percent+/-SD of metabolized T(4) converted to T(3) was 37.2+/-5.8 in normal subjects, 15.7+/-3.1 in non-HD, 12.8+/-1.7 in HD, and 34.0+/-14.7 in RT patients. In contrast, thyroidal T(3) secretion rate was not different between the control and the three patient groups. Thus, it appears that uremia affects thyroid function at several levels: (a) subnormal pituitary TSH response to TRH; (b) possible intrathyroidal abnormalities as suggested by slightly decreased TT(4) and high incidence of goiter; and (c) abnormal peripheral generation of T(3) from T(4). Restoration of renal function with RT resulted in normalization of all parameters of thyroid function with the exception of blunted or absent TSH response to TRH. The latter may be a direct consequence of glucocorticoid administration.

/pdf/thyroid-dysfunction-in-chronic-renal-failure-a-study-of-the-360hvxrwvq.pdf

Thyroid Dysfunction in Chronic Renal Failure: A STUDY OF THE PITUITARY-THYROID AXIS AND PERIPHERAL TURNOVER KINETICS OF THYROXINE AND TRIIODOTHYRONINE

Gonadal dysfunction in uremic men. A study of the hypothalamo-pituitary-testicular axis before and after renal transplantation.

Sera from 2-4 adult animals from each of 16 selected vertebrate species [man, rhesus monkey, cattle, sheep, goat, horse, dog, rat, mice (white and brown), guinea pig, rabbit, pigeon, chicken, trout and perch] were examined for total protein, PBI, serum total T4, T4 dialyzable fraction, resin T3 uptake, the maximal T4 binding capacity of T4 binding proteins and the concentration of free T4 calculated. The pattern of T4 and T3 binding to serum proteins was also examined qualitatively by starch gel, paper and agarose gel electrophoreses in 4 different buffer systems. All animals exhibited T4 and T3 binding to one or more serum proteins. Binding of T4 to prealbumin occurred in sera from man, rhesus monkey, horse, pigeon and chicken. T3 bound to the prealbumin zone only in the pigeon. T4 binding to prealbumin was inhibited by 0.075M barbital in all species capable of binding T4 to this protein except for the pigeons. There was no inter- or intraspecies correlation between the total serum protein concentration ...

Parameters of thyroid function in serum of 16 selected vertebrate species: a study of PBI, serum T4, free T4, and the pattern of T4 and T3 binding to serum proteins.

We investigated the use and possible mechanisms mediating the increased energy expenditure (EE) previously described for rats subjected to total or paradoxical sleep deprivation. Bomb calorimetry of wastes showed that during deprivation the efficiency of energy utilization was not reduced. Estimates of CO2 production by the doubly labelled water method of indirect calorimetry correlated with EE estimated from the caloric value of food, weight change, and wastes and confirmed an increase in EE during deprivation. Core temperatures decreased during the later stages of deprivation, suggesting the hypothesis that excessive heat loss may have required increased EE to protect body temperature. The increased EE could not be explained by the metabolic cost of increase wakefulness, water exposure, or motor activity; an increase in resting EE was indicated. The contribution of the hypothalamic-pituitary-adrenal axis, thyroid gland, and sympathoadrenal system to the mediation of the EE increases was evaluated by measuring the plasma levels of their hormones. Results appear to rule out the first as a mediator. Evidence for the other two was equivocal.

Victor S. Fang

Papers

The effect of neuroleptics on serum prolactin in schizophrenic patients.

Thyroid Dysfunction in Chronic Renal Failure: A STUDY OF THE PITUITARY-THYROID AXIS AND PERIPHERAL TURNOVER KINETICS OF THYROXINE AND TRIIODOTHYRONINE

Gonadal dysfunction in uremic men. A study of the hypothalamo-pituitary-testicular axis before and after renal transplantation.

Parameters of thyroid function in serum of 16 selected vertebrate species: a study of PBI, serum T4, free T4, and the pattern of T4 and T3 binding to serum proteins.

Sleep deprivation in the rat: V. Energy use and mediation.