Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various ...atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17–0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.
Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may ...induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.
The effects of acute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration of a newly developed, potent gonadotropin-releasing hormone antagonist ...induced azoospermia and reduced levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone. These effects coincided with a reduction in outward-directed aggression in all men. Self-reported measures of anxiety and sexual desire revealed less consistent change over time. Measures of anger control, inward-directed anger, and affective state were unaffected.
The recent development of an isometric instrument for the precise quantification of hand force persistence has created a novel opportunity for the evaluation of potential motor asymmetries in ...schizophrenia and their response to treatment. A study of asymmetries in the unmedicated state may provide insight into the pathogenesis of schizophrenia, whereas alterations of asymmetries in response to antipsychotic medication could assist the delineation of a cerebral mechanism for the effects of pharmacotherapy. The hand force persistence of 21 unmedicated patients with schizophrenia was compared to 21 age, gender, and handedness matched normal controls. The effect of neuroleptic treatment on hand force persistence was then evaluated on a subset of 10 patients after at least 30 days of treatment. The anticipated asymmetry was evident in the unmedicated sample that showed impaired right hand force persistence compared to the normal control sample. The prospective comparison showed an alleviation of the asymmetry resulting from an improvement of right hand force persistence with treatment. In addition to providing further support to a primary left hemisphere cerebral involvement in schizophrenia, the present results suggest that prior investigations of motor asymmetry may have been compromised by the study of medicated patients. The apparently paradoxical improvement of motor skill may relate to the substantial number of patients treated with 2nd generation neuroleptic medications which may implicate an improvement in left hemisphere physiology in the cognitive advantages of the novel treatments.
1
Hôpital de la Pitie Salpetriere, Paris, France,
2
Hospital Germans Trias I Pujol, Barcelona, Spain,
3
Allgemeines Krankenhaus St Georg, Hamburg, Germany,
4
Universitatsspital, Zurich, Switzerland,
...5
Auguste‐Viktoria‐Krankenhaus, Berlin, Germany,
6
Ospedale Civico, Lugano, Switzerland,
7
Hôpital Jean Verdier, Bondy, France,
8
Glaxo Wellcome Inc, Research Triangle Park, North Carolina, USA, and
9
HIV and Opportunistic Infections Development Group, Glaxo Wellcome R&D, Greenford Road, Middlesex UB6 0HE, UK
Objectives To evaluate antiretroviral efficacy of abacavir (ABC) in antiretroviral‐experienced patients, by intensifying current antiretroviral therapy (CART) in patients with stable, detectable plasma HIV‐1 RNA.
Methods Thirty‐two European centres recruited HIV‐1 positive patients with ≤ 36 months of CART experience. Patients were randomized to receive either ABC (300 mg twice daily) plus CART (ABC + CART) or ABC placebo plus CART (CART). We assessed efficacy as measured by plasma HIV‐1 RNA and CD4+ cell counts and safety at baseline, weeks 2, 4 and every 4 weeks thereafter until week 48. Protocol‐defined criteria enabled patients to switch to open‐label ABC from week 8 onwards.
Results Ninety‐two patients with a median plasma of 3.66 log10 HIV‐1 RNA copies/mL and a median CD4+ cell count of 408 cells/μL were randomized to ABC + CART and 93 patients with a median plasma of 3.52 log10 HIV‐1 RNA copies/mL and a median CD4+ cell count of 411 cells/μL were randomized to CART. From weeks 8–48, 11 (12%) patients in the ABC + CART group and 34 (37%) patients in the CART group switched to open‐label ABC. At week 48, significantly more patients on ABC + CART (23/92, 25%) than on CART (5/93, 5%) had plasma ≤ 400 HIV‐1 RNA copies/mL (P < 0.001, intent‐to‐treat switch = failure population). Neither duration of previous nucleoside reverse transcriptase inhibitor treatment (up to 18 months) nor prior lamivudine therapy affected ABC efficacy. In the ABC + CART group, 16/25 (64%) patients with the M184V mutation at baseline had ≤ 400 copies/mL or a decrease ≥ 1 log10 copies/mL at week 16. More patients (19/46, 41%) with baseline viral load ≤ 5000 copies/mL had plasma < 400 HIV‐1 RNA copies/mL at 48 weeks than those > 5000 copies/mL (4/44, 9%). CD4+ cell counts increased by 102 cells/μL and 57 cells/μL at week 48 for the ABC + CART and CART groups, respectively (intent‐to‐treat, switch included). ABC addition had minimal impact on the CART safety profile.
Conclusions ABC intensification, in CART‐experienced patients with low viral loads and limited reverse transcriptase mutations, most of whom had previously been on double‐therapy, resulted in a significant and durable plasma HIV‐1 reduction and concomitant increase in CD4+ cell count. The presence of M184V at baseline had minimal impact on the efficacy of ABC.
Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is ...controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a greater degree than either risperidone or haloperidol treatment. This was a double-blind, randomized, controlled, parallel study with neurocognition assessed at baseline, and 8, 24, and 52 weeks. Per protocol, the haloperidol arm was discontinued. Four hundred and fourteen inpatients or outpatients with schizophrenia and schizoaffective disorder were treated with oral olanzapine (
n
=
159), risperidone (
n
=
158), or haloperidol (
n
=
97). Individual domains (executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability) were transformed into composite scores and compared between treatment groups. At the 52-week endpoint, neurocognition significantly improved in each group (
p
<
0.01 for olanzapine and risperidone,
p
=
0.04 for haloperidol), with no significant differences between groups. Olanzapine- and risperidone-treated patients significantly (
p
<
0.05) improved on domains of executive function, learning/memory, processing speed, attention/vigilance, verbal working memory, and motor functions. Additionally, risperidone-treated patients improved on domains of visuospatial memory. Haloperidol-treated patients improved only on domains of learning/memory. However, patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.
BACKGROUND The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. METHODS Sixty-five ...patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. RESULTS The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. CONCLUSIONS These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.Arch Gen Psychiatry. 2000;57:249-258-->
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