Ziprasidone for schizophrenia and severe mental illness.

BACKGROUND: Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs are making important inroads into this approach. Atypical is a widely used term used to describe some antipsychotics which have a low propensity to produce movement disorders and raise serum prolactin. There is some suggestion that the different adverse effect profiles of atypical antipsychotic group make them more acceptable to people with schizophrenia. Ziprasidone is one of the newer atypicals with a high serotonin receptor affinity. OBJECTIVES: To determine the effects of ziprasidone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1999) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies (Pfizer - the manufacturer of ziprasidone - and the manufacturers of all comparator drugs) and first authors of all included trials were contacted. SELECTION CRITERIA: All randomised controlled trials that compared ziprasidone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Data for this compound range from very short (one week) studies of the intramuscular preparation, to trials lasting over six months. For measures of mental state ziprasidone seems more effective than placebo (RR 0.8 CI 0.7-0.9) and as effective as haloperidol (RR 0.8 CI 0.7-1). It is less likely than haloperidol to cause movement disorders (RR 0.4 CI 0.2-0.6), but causes more nausea and vomiting (RR 2.1 CI 1.2-3.8). The injected form of the drug causes more pain at the injection site than haloperidol (RR 5.3 CI 1.3-22). REVIEWER'S CONCLUSIONS: Currently data are limited. Ziprasidone may be an effective antipsychotic with less extrapyramidal effects than haloperidol. It also, however, causes more nausea and vomiting than the typical drugs, and, at present, there is no data suggesting that it is different to other atypical compounds. Well planned, conducted and reported long term randomised trials are needed if ziprasidone is to be accepted into everyday use.

Molindone for schizophrenia and severe mental illness.

BACKGROUND: Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs is making important inroads into this approach. 'Atypical' is a term widely used to describe some antipsychotics which have a low propensity to produce movement disorders, sedation and raised serum prolactin. There is some suggestion that the different adverse effect profiles of the atypical antipsychotic group make them more acceptable to people with schizophrenia. Molindone has a similar profile to quetiapine (a novel atypical antipsychotic), with very low binding to all receptors. Some authors have suggested that molindone is safer than other 'typical' antipsychotics in that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as an atypical antipsychotic. OBJECTIVES: To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. The manufacturer of molindone and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences (WMD) were calculated. All data were inspected for heterogeneity. MAIN RESULTS: Thirteen studies were included in the review. Data for this compound range from very short (10 day) studies of the intramuscular preparation to trials lasting over three months. For measures of global state available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics no difference in effectiveness was evidenced (doctors' RR 1.13, CI 0.69 to 1.86; nurses' RR 1.23, CI 0.82 to 1.86). It is no more or less likely than typical drugs to cause movement disorders, but causes significantly more weight loss (RR 2.78, CI 1.10 to 6.99). REVIEWER'S CONCLUSIONS: The strength of the evidence relating to this compound is limited, owing to small sample size, poor study design, limited outcomes and incomplete reporting. Molindone may be an effective antipsychotic; however, its adverse effect profile does not differ significantly from that of typical antipsychotics, apart from the event of weight loss. At present there is no evidence to suggest that it may have an atypical profile.

Ziprasidone for schizophrenia and severe mental illness.

BACKGROUND: Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs are making important inroads into this approach. Atypical is a widely used term used to describe some antipsychotics which have a low propensity to produce movement disorders, sedation and raised serum prolactin. There is some suggestion that the different adverse effect profiles of the atypical antipsychotic group make them more acceptable to people with schizophrenia. Ziprasidone is one of the newer atypicals with a high serotonin/dopamine receptor affinity. OBJECTIVES: To determine the effects of ziprasidone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1995) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled trials that compared ziprasidone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Data for this compound range from very short (1 week) studies of the intramuscular preparation, to trials lasting over six months. For measures of mental state ziprasidone seems more effective than placebo (RR 0.8 CI 0.7-0.9) and as effective as haloperidol (RR 0.8 CI 0.7-1). It is less likely than haloperidol to cause movement disorders (RR 0.4 CI 0.2-0.6), but may cause more nausea and vomiting (RR 2.1 CI 1.2-3.8). The injected form of the drug may cause more pain at the injection site than haloperidol (RR 5.3 CI 1.3-22). REVIEWER'S CONCLUSIONS: Currently data are limited. Ziprasidone may be an effective antipsychotic with less extrapyramidal effects than haloperidol. It also may, however, cause more nausea and vomiting than the typical drugs, and, at present, there is no data suggesting that it is different to other atypical compounds. Well planned, conducted and reported long term randomised trials are needed if ziprasidone is to be accepted into everyday use.

Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRalpha coreceptor-specific.

Neurturin (NRTN) and glial cell line-derived neurotrophic factor (GDNF) are members of a family of trophic factors with similar actions in vitro on certain neuronal classes. Retrograde transport of GDNF and NRTN was compared in peripheral sensory, sympathetic, and motor neurons to determine whether in vivo these factors are transported selectively by different neuronal populations. After sciatic nerve injections, NRTN was transported by sensory neurons of the dorsal root ganglion (DRG). Competition studies demonstrated only limited cross-competition between NRTN and GDNF, indicating selective receptor-mediated transport of these factors. By using immunohistochemistry, we identified two populations of NRTN-transporting DRG neurons: a major population of small, RET-positive, IB4-positive, non-TrkA-expressing neurons that also show the ability to transport GDNF and a minor population of calretinin-expressing neurons that fail to transport GDNF. Spinal motor neurons in the adult showed relatively less ability to transport NRTN than to transport GDNF, although NRTN prevented the cell death of neonatal motor neurons in a manner very similar to GDNF (Yan et al., 1995) and persephin (PSPN) (Milbrandt et al., 1998). Last, NRTN, like GDNF, was not transported to sympathetic neurons of the adult superior cervical ganglion (SCG) after injection into the anterior eye chamber. These data reveal a high degree of functional selectivity of GDNF family receptor-alpha (GFRalpha) coreceptor subtypes for NRTN and GDNF in vivo.

Persephin, a novel neurotrophic factor related to GDNF and neurturin.

A novel neurotrophic factor named Persephin that is approximately 40% identical to glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) has been identified using degenerate PCR. Persephin, like GDNF and NTN, promotes the survival of ventral midbrain dopaminergic neurons in culture and prevents their degeneration after 6-hydroxydopamine treatment in vivo. Persephin also supports the survival of motor neurons in culture and in vivo after sciatic nerve axotomy and, like GDNF, promotes ureteric bud branching. However, in contrast to GDNF and NTN, persephin does not support any of the peripheral neurons that were examined. Fibroblasts transfected with Ret and one of the coreceptors GFRalpha-1 or GFRalpha-2 do not respond to persephin, suggesting that persephin utilizes additional, or different, receptor components than GDNF and NTN.

Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex.

The glial cell line-derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRalpha1-GFRalpha4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the former orphan receptor GFRalpha3-RET. Artemin is a survival factor for sensory and sympathetic neurons in culture, and its expression pattern suggests that it also influences these neurons in vivo. Artemin can also activate the GFRalpha1-RET complex and supports the survival of dopaminergic midbrain neurons in culture, indicating that like GDNF (GFRalpha1-RET) and NTN (GFRalpha2-RET), Artemin has a preferred receptor (GFRalpha3-RET) but that alternative receptor interactions also occur.

IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.

We have tested the role of glial cell line-derived neurotrophic factor (GDNF) in regulating a group of putatively nociceptive dorsal root ganglion (DRG) neurons that do not express calcitonin gene-related peptide (CGRP) and that downregulate the nerve growth factor (NGF) receptor tyrosine kinase, TrkA, after birth. We show that mRNA and protein for the GDNF receptor tyrosine kinase, Ret, are expressed in the DRG in patterns that differ markedly from those of any of the neurotrophin receptors. Most strikingly, a population of small neurons initiates expression of Ret between embryonic day 15.5 and postnatal day 7.5 and maintains Ret expression into adulthood. These Ret-expressing small neurons are selectively labeled by the lectin IB4 and project to lamina IIi of the dorsal horn. Ret-expressing neurons also express the glycosyl-phosphatidyl inositol-linked (GPI-linked) GDNF binding component GDNFR-alpha and retrogradely transport 125I-GDNF, indicating the presence of a biologically active GDNF receptor complex. In vitro, GDNF supports the survival of small neurons that express Ret and bind IB4 while failing to support the survival of neurons expressing TrkA and CGRP. Together, our findings suggest that IB4-binding neurons switch from dependence on NGF in embryonic life to dependence on GDNF in postnatal life and are likely regulated by GDNF in maturity.

Regional variation in the ratio of sigma 1 to sigma 2 binding in rat brain.

In vitro binding experiments were performed to determine whether known subtypes of the putative sigma receptor exhibit a differential distribution across brain regions and species. Rat brains were dissected into nine regions, pooled, and used to prepare membranes for ligand binding studies. Whole guinea pig brains were prepared in an identical manner for comparison to rat. sigma 1 Receptors were labeled with [3H](+)-pentazocine. sigma 2 Receptors were labeled with [3H]1,3-di-o-tolylguanidine (DTG) in the presence of 1 microM dextrallorphan to mask sigma 1 sites. Non-specific binding was determined in the presence of 10 microM haloperidol. Filtration and scintillation spectroscopy provided the binding values. The experiment revealed marked variation in the ratio of sigma 2 to sigma 1 binding across brain regions ranging from a low of 1.63 in the hindbrain to 3.51 in the cerebellum, that result mainly differences in the density of the receptors. Scatchard analysis on membranes derived from the hindbrain and cortex suggested that the effects were due primarily to regional differences in densities of receptor subtypes rather than different affinities. Guinea pig brain showed a marked preponderance of sigma 1 receptors with a ratio (sigma 2/sigma 1) of 0.67. These findings demonstrate that sigma 1 and sigma 2 receptors are differentially distributed in rat brain.