Initiation of clozapine therapy in a patient with preexisting leukopenia: a discussion of the rationale of current treatment options.

Clozapine remains the most effective agent for diminishing or eliminating psychotic symptoms in treatment-resistant patients. However, among such patients, a small percentage (<3.0%) develops clozapine-induced granulocytopenia (CIG). In spite of the fact that lithium and granulocyte colony stimulating factor (G-CSF) have been shown to reverse CIG, many such patients are consigned to treatment with antipsychotic agents that have failed in the past. Apparently, their physicians are not aware that these patients can be salvaged for ongoing clozapine treatment. We report the effectiveness of lithium in reversing CIG in a young man with preexisting mild granulocytopenia. The rapidity of onset of leukocyte depletion is discussed in light of previously hypothesized autoimmune mechanisms of CIG. This case dramatizes the importance of lithium (or G-CSF) augmentation in those patients to maintain clozapine treatment so that their neutropenia can be reversed, and they can continue to benefit from the unique antipsychotic qualities of clozapine.

Meal patterns and food intakes of ground squirrels during circannual cycles.

Meal patterns in ground squirrels (Spermophilus lateralis) were recorded repeatedly over the course of endogenous circannual body weight cycles, with most data coming from the weight-gain phase. No manipulations were made, and the conditions were kept as constant as possible. Meal patterns were related to the level of food intake at each observation period. When the animals ate more, the most noticeable change was an elevated meal frequency. There were also some increases in meal size and the rate of ingestion. Postprandial correlations were generally positive, but rather variable and did not increase significantly when the animals ate more. On average 57% of the total intake occurred during the light phase of the LD 12:12 cycle. No systematic changes in the diurnality of feeding were detected. The meal patterns of hibernators when they are spontaneously hyperphagic show some resemblance to those seen in animals given exogenous insulin.

Meal patterns of dormice.

Meal patterns were studied in dormice (Glis glis) kept at an ambient temperature of 25 degrees C. At this temperature there is no prolonged hibernation and the periodicity of cycles of food intake and body weight is about 2 months. The data on meal patterns were related to the level of food intake during repeated observation periods. The most pronounced changes were in meal frequency, but there were also significant increases in meal size when the animals ate more. Postprandial correlations were low and insignificant in most animals. Nevertheless, there was a significant strengthening of these correlations at times the animals ate more. Rate of ingestion remained stable. The dormice ate 70% of their food in the dark phase of the LD 12:12 cycle. Meal size in the night and day were similar and remained so when the animals ate more; meal frequency increased in both the night and the day at these times. There was no evidence that long-term seasonally-related changes in feeding in hibernators depend on the same neuroendocrine and metabolic mechanisms that are involved in circadian feeding cycles.

Suprachiasmatic nuclei influence circannual and circadian rhythms of ground squirrels.

Golden-mantled ground squirrels, maintained under constant conditions of photoperiod and temperature sustained lesions of the suprachiasmatic nuclei (SCN) or of the medial basal hypothalamus. Destruction of the SCN eliminated or disrupted circadian activity rhythms and shortened the period of the circannual reproductive cycle. Circannual body weight cycles were eliminated or disrupted in several SCN-lesioned animals and one squirrel had a 3- to 5-mo body weight rhythm; however, most SCN-lesioned squirrels with disrupted circadian activity cycles manifested normal circannual body weight rhythms. The SCN are important for circadian organization of locomotor activity of this diurnal rodent, but the generation and expression of circannual body weight and reproductive rhythms can proceed in the absence of coherent circadian organization. The SCN are less essential for the generation and expression of circannual than of circadian cycles.

Circannual body weight rhythms of ground squirrels: role of gonadal hormones.

The influence of ovarian and testicular hormones on circannual body weight cycles was assessed in golden-mantled ground squirrels (Spermophilus lateralis), maintained in a LD 14:10 photoperiod at 23 degrees C. Animals were gonadectomized or sham operated at 47 days of age and implanted with empty capsules or capsules filled with estradiol benzoate (EB) or testosterone propionate (TP). Body weight, food intake, and reproductive condition were recorded at weekly intervals. Gonadectomized and intact squirrels of both sexes manifested robust circannual rhythms of body weight; cyclic secretion of gonadal hormones was not necessary for the expression of this circannual cycle. Intact and gonadectomized males weighed substantially more than their female counterparts but only during part of the annual cycle. This sex difference waxed and waned on a circannual basis in the absence of concurrent gonadal hormone secretions. EB phase-delayed attainment of peak body weights in ovariectomized squirrels but did not affect timing of trough body weights. EB increased the amount of food consumed by ovariectomized squirrels particularly during the weight gain phase. TP accelerated attainment of trough body weights in orchidectomized animals. Gonadal hormones modify the magnitude and timing of body weight peaks and troughs but are not necessary for the generation or expression of the circannual body weight cycle or for the sex difference in this cycle.

Circannual rhythms of plasma testosterone and luteinizing hormone levels in golden-mantled ground squirrels (Spermophilus lateralis).

Male squirrels, born approximately June 1 and kept under constant conditions of photoperiod (14 h of light per day) and temperature (23 +/- 2 degrees C) from birth, manifested circannual rhythms in plasma testosterone (T) and luteinizing hormone (LH) levels. Blood samples were collected once per month for 22 months and hormone levels determined by radioimmunoassay. Testosterone levels were low or undetectable ( less than or equal to 0.05 ng/ml) between October and January of the first year, and began increasing in February and peaked during April and May (approx. 4.5 ng/ml). By August of the second year T had declined to low levels which were maintained through January (0.05 ng/ml). The cycle then repeated, with T titers elevated during April and May of the second year. LH levels were undetectable (less than or equal to ng/ml) throughout most of the first 8 months of life; LH peaks were reached by individual animals between March and July. There was a close correspondence between seasonal peaks and troughs of testosterone and those in LH. The circannual pattern of plasma T and LH also was documented for a group of field-trapped males (less than or equal to 11 months old) maintained under similar conditions and bled at monthly intervals for 14 consecutive months. Rhythms of plasma T and LH persisted with a period of 11 to 12 months under constant conditions and thus qualify as circannual cycles.

Photoperiodic inhibition of testicular development is mediated by the pineal gland in white-footed mice.

White-footed mice were maintained in short or long photoperiods from birth to 60 days of age (10 h vs. 14 h of light per day). Testes weights and spermatogenesis were substantially reduced in short daylengths. Pinealectomy at 5-7 days of age eliminated the suppressive effect of photoperiod on the reproductive system. However, testicular development was not retarded in intact males kept from 25 to 60 days of age in short daylengths. Exposure to short daylengths prior to 25 days of age contributes to photoperiodic inhibition of testicular development. Removal of the pineal gland did not consistently affect gonadal maturation in long photoperiods. The pineal gland transduces the effects of short daylengths on reproductive development. Some effects of long daylengths on the neuroendocrine axis of white-footed mice may also be mediated by the pineal gland.

Efficiency of food utilization during body weight gain in dormice (Glis glis).

During spontaneous body weight gain in dormice, Glis glis, progressive increases in the efficiency of food utilization as defined by weight gain (g)/food intake (g), and parallel increases in mean daily food intake were observed. Towards the end of the weight gain period, there was an abrupt drop in feeding efficiency with no significant change in food intake even when the latter was expressed relative to an index of each animal's "metabolic mass" (body weightkg0.62). Animals whose body weight increases followed a return to ad lib feeding after prolonged food restriction showed marked decreases in feeding efficiency from initially high values which were independent of changes in food intake. These results are discussed in relation to the sliding set point concept of body weight regulation in hibernators.