Dropout rates in randomised antipsychotic drug trials.

RATIONALE: It has been assumed that new atypical drugs improve treatment compliance due to fewer adverse effects. Data supporting this assumption are scarce. OBJECTIVES: The aim of this study was to study attrition rates in randomised controlled trials of oral administration of conventional antipsychotic drugs, atypical antipsychotic drugs and placebo. METHODS: The database of the Schizophrenia Module of the Cochrane Library was utilised for the present study. The data in the Cochrane Module are collected by identifying relevant randomised controlled trials from several electronic databases and other sources. Number of dropouts was defined as patients leaving the study preterm due to any reason. RESULTS: Data from 328 treatment groups, consisting of 18,585 randomised subjects from 163 drug trials, were entered in the analysis. One-third of the subjects had dropped out of the trials. The dropout rates significantly increased for each calendar year. Year of trial publication, type of drug and trial length remained statistically significant contributors to dropout rates. In a model incorporating year of publication and trial length, placebo groups and groups treated with conventional antipsychotics had significantly higher attrition rates than groups treated with atypical drugs. When clozapine-treated groups were excluded from the analysis, no statistically significant advantage for atypical drugs over conventional drugs remained. CONCLUSIONS: Trial data implicate that a better compliance can be achieved by favouring atypical drugs rather than conventional alternatives in the treatment of schizophrenia. However, this effect is found only when groups treated with the atypical antipsychotic clozapine are included in the analysis. Our study did not find evidence for a statistically significant superiority in acceptability of novel atypical drugs when compared to conventional antipsychotics.

Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study.

BACKGROUND: The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol. METHOD: Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients. CONCLUSION: This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.

Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia.

We compared the cerebrospinal fluid (CSF) cytology of 30 acutely psychotic patients at the initial phase of their hospital treatment with that of 46 control individuals with no psychiatric disorder or central nervous system (CNS) disease. The cytological profile of May-Grünwald-Giemsa stained CSF cell slides of the patients was significantly different from that of the control population. The most striking finding was a significantly increased frequency of lymphoid cells showing morphological features of activation/stimulation and a decreased proportion of normal small lymphocytes. Many of the cells with aberrant morphology displayed structural details similar to those of the 'P cells' previously described in the blood of schizophrenic patients. The patients' CSF also contained elevated proportions of monocytes/macrophages, some of which were found in 'rosettes' with activated lymphocytes indicating an increased intercellular adhesion. Possible pathogenic mechanisms behind lymphocyte activation and macrophage dominance in the CSF of acutely ill psychotic patients are discussed.

Mitchell B. Balter Award. Human leukocyte antigen-A1 predicts a good therapeutic response to clozapine with a low risk of agranulocytosis in patients with schizophrenia.

Several studies indicate an association between human leukocyte antigens (HLA) and clozapine-induced agranulocytosis. The authors have previously reported a significantly increased frequency of HLA-A1 among patients with schizophrenia who do not respond to conventional drugs, but do respond to clozapine treatment. In this study, the authors addressed the question of whether the same association is found in patients developing granulocytopenia or agranulocytosis. The frequency of the HLA-A1 allele in patients with clozapine-induced agranulocytosis or granulocytopenia was low (11.5%), whereas HLA-A1 was associated with a good therapeutic response to clozapine at an allele frequency of 58%. The frequency of HLA-A1 is 20% in the Finnish population. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and, thus, enable defining a subgroup of patients with schizophrenia in whom clozapine treatment could be started early to stop the disease from progressing.

Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study.

1. The atypical antipsychotic risperidone may constitute an alternative to clozapine, the current treatment of choice for refractory schizophrenia. The objectives of this study were to evaluate the effectiveness of risperidone in comparison to clozapine in everyday practice and to assess the feasibility of a pragmatic trial procedure. 2. Patients were randomly assigned to open-label clozapine or risperidone treatment for 10 weeks and treatment outcomes were assessed blindly. Twenty-one patients were recruited and nineteen entered the randomized phase. 3. Five of 10 participants allocated to clozapine and one of nine risperidone participants dropped out before study completion. Five clozapine patients and six risperidone patients achieved clinical improvement, defined as a 20% decrease in the Positive and Negative Symptom Scale (PANSS) total score. No significant differences between the groups were detected in baseline or endpoint positive or negative symptoms, disease severity, or global or social functioning scores. Patients' opinion on the drugs did not differ between groups. 4. The findings of the intention-to-treat analysis of this study corroborates previous findings that risperidone may be equally effective as clozapine, and supports the feasibility and need of a multicenter randomized pragmatic trial with sufficient power to detect differences between treatments.

An artifactual in situ hybridization signal associated with apoptosis in rat embryo.

We report an artifactual in situ hybridization (ISH) labeling pattern in embryonic rat tissues. It is caused by a short multiple cloning site-derived sequence incorporated into the RNA probes by in vitro transcription of templates cloned into pBluescript or its descendants. The artifact was seen in tissues in which programmed cell death (apoptosis) takes place during embryogenesis, i.e., in the mesonephric area, developing nervous system, interdigital mesenchyme of the hand plate, and permanent kidney. Labeling of the radioactive ISH with TUNEL verified the co-localization of the artifactual hybridization signal with cells at early stages of apoptosis. Even though the identity of the hybridization target in apoptotic cells remains unknown, it might be highly species-specific, because this artifact was never observed in mouse tissues.

Positive treatment effect of estradiol in postpartum psychosis: a pilot study.

BACKGROUND: Postpartum illnesses with psychiatric symptoms and serious adverse sequelae are highly prevalent during the childbearing years. Despite multiple medical contacts, these illnesses often remain unidentified and untreated. To study the association between estradiol and puerperal psychosis, we measured serum concentration of estradiol and performed an open-label trial of physiologic 17beta-estradiol in women with this disorder. METHOD: Ten women with ICD-10 psychosis with postpartum onset consecutively recruited from a psychiatric duty unit were studied. Serum estradiol concentration was measured at baseline and weekly during sublingual 17beta-estradiol treatment for 6 weeks. The treatment effect was evaluated by a clinician-rated psychiatric symptom scale (the Brief Psychiatric Rating Scale [BPRS]). RESULTS: The baseline serum estradiol levels (mean = 49.5 pmol/L; range, 13-90 pmol/L) were even lower than the threshold value of gonadal failure, and the patients exhibited high scores on the psychiatric symptom scale (mean BPRS total score = 78.3; range, 65-87). During the first week of 17beta-estradiol treatment, psychiatric symptoms diminished significantly (BPRS score decreased to a mean of 18.8, p < .001). Until the end of the second week of treatment, serum estradiol concentrations rose to near the values normally found during the follicular phase, and the patients became almost free of psychiatric symptoms. CONCLUSION: The reversal of psychiatric symptoms in all patients by treating documented estradiol deficiency suggests that estradiol plays a role in the pathophysiology and may have a role in the treatment of this condition. There was a rebound of psychotic symptoms in the 1 patient who discontinued estradiol treatment. Given the small number of patients, this area deserves further study.

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia.

The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process.

Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients.

Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies.

Association between oestradiol and puerperal psychosis.

OBJECTIVE: Postpartum psychiatric disorders with long-lasting adverse sequelae are common during the childbearing years. These disorders can be severe and resistant to conventional psychiatric treatment methods. We present two consecutive cases with puerperal psychosis who were refractory to conventional treatment methods but responded successfully to oestrogen therapy. METHOD: Serum oestradiol concentration was measured by radioimmunoassay and the documented oestradiol deficiency replaced with physiological oestradiol sublingually. The treatment effect was evaluated by the Brief Psychiatric Rating Scale. RESULTS: In both cases the baseline oestradiol concentration was low (28 and 69 pmol/L). During the treatment with oestradiol, there was a concomitant elevation of the concentration of serum oestradiol, which coincided with the decline in psychotic symptoms. CONCLUSION: The observation of low serum oestradiol together with psychotic symptoms and successful treatment with oestradiol suggests that oestradiol may have a causal relevance to puerperal psychosis and significance in the treatment of this condition.

BMP-4 affects the differentiation of metanephric mesenchyme and reveals an early anterior-posterior axis of the embryonic kidney.

Bone morphogenetic protein-4 (BMP4), a member of the transforming growth factor-beta (TGF-beta) family, regulates several developmental processes during animal development. We have now studied the effects of BMP-4 in the metanephric kidney differentiation by using organ culture technique. Human recombinant BMP-4 diminishes the number of ureteric branches and changes the branching pattern. Our data suggest that BMP-4 affects the ureteric branching indirectly via interfering with the differentiation of the nephrogenic mesenchyme. The clear positional preference of the defects to posterior mesenchyme might reflect an early anterior-posterior patterning of the metanephric mesenchyme. The smooth muscle alpha-actin expressing cell population around the ureteric stalk, highly expressing Bmp-4 mRNA, is also expanded in kidneys treated with BMP-4. Thus, BMP-4 may be a physiological regulator of the development of the periureteric smooth muscle layer and ureteric elongation.

Regulation of cell fate decision of undifferentiated spermatogonia by GDNF.

The molecular control of self-renewal and differentiation of stem cells has remained enigmatic. Transgenic loss-of-function and overexpression models now show that the dosage of glial cell line-derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis. Gene-targeted mice with one GDNF-null allele show depletion of stem cell reserves, whereas mice overexpressing GDNF show accumulation of undifferentiated spermatogonia. They are unable to respond properly to differentiation signals and undergo apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors are regularly formed in older GDNF-overexpressing mice. Thus, GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.

Role of estradiol in puerperal psychosis.

RATIONALE: Postpartum period has been considered a time of increased risk for the development of psychiatric disorders with long-lasting adverse consequences. Psychoses are the most severe of these illnesses and can be resistant to psychiatric medication. OBJECTIVE: We present two women with puerperal psychosis who had low serum estradiol, were refractory to neuroleptic medication but responded successfully to estradiol treatment. METHODS: Serum estradiol concentration was measured at baseline and during the treatment with sublingual 17-beta estradiol. Treatment effect was evaluated using Brief Psychiatric Rating Scale. RESULTS: Both patients had a low pretreatment estradiol concentration (28 and 54 pmol/l). During treatment with estradiol, the rise in serum estradiol coincided with a decline of psychotic symptoms. Discontinuation of estradiol treatment resulted in a rebound of florid psychotic symptoms in both cases. CONCLUSIONS: Estradiol may have a causal relation to postpartum psychosis and significance in the treatment of this illness.

Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes.

OBJECTIVE: There have been numerous reports of organic or structural abnormalities in the central nervous system (CNS) of patients with schizophrenia. Given that pathological conditions in the CNS are frequently reflected in the cell profiles of CSF, the authors compared the cytology of CSF from schizophrenic patients with that from a reference population in order to find out trails of elementary pathogenetic events in this serious psychiatric disease. METHOD: CSF samples from 35 patients with acute schizophrenia and 46 comparison subjects were prepared by Millipore filtration. The total and differential counts of CSF mononuclear cells were performed by light microscopy. RESULTS: At the beginning of treatment, the proportion of mononuclear phagocytes/macrophages in the patients' CSF was significantly higher than that in the comparison subjects. During treatment with conventional neuroleptic medication, the cytology returned to normal in several patients. CONCLUSIONS: The high proportion of macrophages in schizophrenia without a significantly higher total cell count may reflect neurodevelopmental disorder, a neurodegenerative process, or subtle CNS immunoactivation with mobilization of microglia.

Mesonephric kidney--a stem cell factory?

Mesonephros is a vestige, transient renal organ that functions only during embryonic development. The anatomy, position and even cellular fate of the mesonephric kidney varies drastically among mammalian species. The origin of mesonephros from intermediate mesoderm and the dependence of its differentiation on the nephric or Wolffian duct have been well established. Commonly accepted is also the mesonephric origin of epididymal ducts of the male reproductive tract. Recently, upon the more profound understanding of the molecular mechanisms involved in the development of the permanent mammalian kidney, some light has been shed over the molecular events taking place during the mesonephric development as well. Because of the functional and structural similarities between the mesonephric and metanephric kidneys, it is not surprising that many molecules regulating metanephric development are also activated during mesonephric development. However, the multifunctional nature of mesonephros has been unexpected. First, it serves as an embryonic secretory organ, in some mammalian species more so than in others. It is thereafter removed by programmed cell death. Second, it is a source of multiple stem cells including somatic cells in the male gonad, vascular endothelial cells, and hematopoietic stem cells. Thus, mesonephros is a challenging model for studies on epithelial differentiation and organogenesis, regulation of apoptosis, sex determination and stem cell differentiation. In this review, we focus in the molecular and stem cell aspects in the differentiation of the mammalian mesonephros.

Effect of oestradiol on postpartum depression.

RATIONALE: The months following childbirth are a time when women are susceptible to depressive disorders, which may be severe and have long-lasting serious adverse consequences. The illnesses remain often unrecognized and untreated, and can be resistant to conventional psychiatric treatment methods. OBJECTIVE: We report two patients with postpartum depression, who had low serum oestradiol together with psychiatric symptoms, and who responded successfully to treatment with oestradiol. METHODS: The serum oestradiol concentration was measured at baseline and weekly during treatment with sublingual 17-beta oestradiol for 8 weeks. The treatment effect was evaluated using the Montgomery-Asberg Depression Rating Scale. RESULTS: Both patients had a low pretreatment oestradiol concentration (36-120 and 31 pmol/l). During treatment with oestradiol, the decline of depressive symptoms coincided with a rise in serum oestradiol. CONCLUSIONS: Oestradiol may be causally related to postpartum depression and have significance in the treatment of this condition.

Circadian rhythm of white blood cells during clozapine treatment.

RATIONALE: The atypical antipsychotic clozapine is effective in the treatment of patients with refractory schizophrenia. It carries a well-known risk of neutropenia and agranulocytosis, which necessitates the immediate discontinuation of clozapine. OBJECTIVE: We report a patient who developed neutropenia on clozapine, but behind the cell count decrease showed to be a diurnal variation of the white blood cells (WBC). METHODS: Due to the lack of efficacy of subsequent treatment of conventional and other atypical neuroleptics, treatment with clozapine was restarted after discontinuation. When the morning count of WBC began to fall, WBC count was repeated in the afternoons. RESULTS: Careful blood cell monitoring showed a pronounced diurnal variation of WBC (2.9-4.2x10(9)/l in the morning and 3.6-7.1x10(9)/l in the afternoon) and granulocytes (0.8-1.4x10(9)/l and 2.9-5.5x10(9)/l, respectively). CONCLUSIONS: Some patients may thus have a spuriously low cell count and may be unnecessarily denied effective treatment.

Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free patients with schizophrenia.

The aim of this study was to replicate our earlier finding of elevated angiotensin-converting enzyme (ACE) in cerebrospinal fluid (CSF) in schizophrenia and to elucidate the role of neuroleptic treatment in this phenomenon. Drug-free and medicated patients with acute schizophrenic psychoses, as well as healthy controls were recruited. Levels of ACE were measured in CSF and serum from 7 drug-free patients, 36 neuroleptic-treated patients, and 19 healthy control subjects. Although ACE levels in CSF did not differ between patients and controls, the drug-free patients showed significantly lower levels than the neuroleptic-treated patients. Serum ACE did not differ between groups. The elevation of CSF ACE may be more prominent in patients with deficit symptoms than in those with mainly psychotic symptoms. The possible enhancement of CSF ACE production or solubility by neuroleptic treatment is discussed. Elevated ACE levels in CSF may, together with other possible factors, cause polydipsia, stimulate secretion of arginine vasopressin, and even affect neuron growth and differentiation in schizophrenic psychoses.

Structure of the human macrophage MARCO receptor and characterization of its bacteria-binding region.

The primary structure of human macrophage receptor with collagenous structure (MARCO) was determined from cDNA clones and shown to be highly similar to that of mouse (Elomaa, O., Kangas, M., Sahlberg, C. , Tuukkanen, J., Sormunen, R., Liakka, A., Thesleff, I., Kraal, G., and Tryggvason, K. (1995) Cell 80, 603-609). Features such as potential carbohydrate attachment sites in the extracellular spacer domain III and the interruption of Gly-Xaa-Yaa repeats in the collagenous domain IV were conserved between the two species. However, the human MARCO polypeptide chain lacked the intracellular cysteine present in mouse, as well as two extracellular cysteines that form interchain disulfide bonds in the murine protein. In situ hybridization showed MARCO to be strongly expressed in macrophages of several tissues of human individuals with sepsis. No expression was observed in other cell types. The bacteria-binding region of MARCO was determined in binding studies with full-length and truncated variants of MARCO, and localized to a region proximal to the cysteine-rich part of the COOH-terminal domain V. The intrachain disulfide bond pattern of domain V was established showing that these bonds are between cysteine pairs C1-C5, C2-C6, and C3-C4.

Association between HLA-A1 allele and schizophrenia gene(s) in patients refractory to conventional neuroleptics but responsive to clozapine medication.

We report an association between HLA-A1 allele and a subgroup of schizophrenic patients refractory to conventional neuroleptic treatment but responsive to clozapine. The frequency of HLA-A1 was 58% among the schizophrenic patients not responding to conventional treatment but responsive to clozapine but only 10.5% among the patients responding to conventional neuroleptics. The HLA-A1 occurs in 20% of the random Finnish population. Our results indicate that HLA-A1 defines a subgroup of schizophrenic patients with a selective response to neuroleptics.