Loxapine to control agitation during weaning from mechanical ventilation.

BACKGROUND: Weaning from mechanical ventilation (MV) may be impeded by the occurrence of agitation. Loxapine has the ability to control agitation without affecting spontaneous ventilation. The aim of this study was to establish whether loxapine would reduce MV weaning duration in agitated patients. METHODS: We performed a multicentre, double-blind, placebo-controlled, parallel group, randomised trial. Patients who were potential candidates for weaning but exhibited agitation (Richmond Agitation-Sedation Scale score ≥ 2) after sedation withdrawal were randomly assigned to receive either loxapine or placebo. In case of severe agitation, conventional sedation was immediately resumed. The primary endpoint was the time between first administration of loxapine or placebo and successful extubation. RESULTS: The trial was discontinued after 102 patients were enrolled because of an insufficient inclusion rate. Median times to successful extubation were 3.2 days in the loxapine group and 5 days in the placebo group (relative risk 1.2, 95% CI 0.75-1.88, p = 0.45). During the first 24 h, sedation was more frequently resumed in the placebo group (44% vs 17%, p = 0.01). CONCLUSIONS: In this prematurely stopped trial, loxapine did not significantly shorten weaning from MV. However, loxapine reduced the need for resuming sedation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01193816 . Registered on 26 August 2010.

Modelling schizophrenia using human induced pluripotent stem cells.

Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

The antipsychotic drug loxapine is an opener of the sodium-activated potassium channel slack (Slo2.2).

Sodium-activated potassium (K(Na)) channels have been suggested to set the resting potential, to modulate slow after-hyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K(Na) channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 µM was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC(50) = 4.4 µM and EC(50) = 2.9 µM, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the single-channel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K(Na) channels and to increase the rheobase of action potential. This study identifies new K(Na) channel pharmacological tools, which will be useful for further Slack channel investigations.

Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder.

OBJECTIVE: To describe the efficacy and safety of inhaled loxapine, a new formulation of an older antipsychotic being developed for the treatment of agitation associated with schizophrenia or bipolar disorder. DATA SOURCES: A literature search was conducted by querying http://www.pubmed.gov, http://www.fda.gov, http://www.accessdata.fda.gov/scripts/cder/drugsatfda and http://www.clinicaltrials.gov for the search terms 'loxapine' AND 'agitation', 'inhaled loxapine', 'staccato loxapine'. The manufacturer was asked to provide copies of posters presented at national and international meetings, and to provide any copies of papers currently in press. STUDY SELECTION: All available reports of studies were identified. DATA EXTRACTION: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports. DATA SYNTHESIS: Inhaled loxapine is delivered using a handheld device that produces a thermally generated condensation aerosol free of excipients or propellants. Time to maximum plasma concentration is approximately 2 min. In two phase III studies (one in subjects with schizophrenia, the other in subjects with bipolar disorder) inhaled loxapine 5 and 10 mg were both superior to placebo as early as 10 min after administration, as measured using the Positive and Negative Syndrome Scale excited component. Pooling together data from three efficacy studies, NNT for response for inhaled loxapine 5 or 10 mg vs. placebo were 4 (95% CI 3-5) and 3 (95% CI 3-4), respectively, with response defined as achieving a Clinical Global Impressions - Improvement score of 1 or 2 at 2 h postdose. This effect size is in the range observed for intramuscular administration of other antipsychotics for agitation associated with schizophrenia or bipolar disorder. There were no clinically relevant signals for the emergence of extra-pyramidal side effects or akathisia. The most commonly encountered adverse event appears to be dysgeusia (distorted taste sense or bad taste), with a NNH vs. placebo of 10 (95% CI 7-22) or 12 (95% CI 8-26), for loxapine 10 or 5 mg, respectively. CONCLUSIONS: Inhaled loxapine appears efficacious and tolerable for the treatment of agitation associated with schizophrenia or bipolar disorder. Although simple to self-administer, inhaled loxapine requires a degree of cooperation from the recipient and thus will not be a substitute for an injection during psychiatric emergencies when the patient is actively refusing medication treatment. The efficacy and safety of inhaled loxapine in elderly patients and in outpatient care settings remain to be established.

A Novel Dibenzoxazepine Attenuates Intracellular Salmonella Typhimurium Oxidative Stress Resistance.

Salmonella enterica serovar Typhimurium is the leading cause of invasive nontyphoidal salmonellosis. Additionally, the emergence of multidrug-resistant S. Typhimurium has further increased the difficulty of controlling its infection. Previously, we showed that an antipsychotic drug, loxapine, suppressed intracellular Salmonella in macrophages. To exploit loxapine's antibacterial activity, we simultaneously evaluated the anti-intracellular Salmonella activity and cytotoxicity of newly synthesized loxapine derivatives using an image-based high-content assay. We identified that SW14 exhibits potent suppressive effects on intramacrophagic S. Typhimurium with an 50% effective concentration (EC50) of 0.5 µM. SW14 also sensitized intracellular Salmonella to ciprofloxacin and cefixime and effectively controlled intracellular multidrug- and fluoroquinolone-resistant S. Typhimurium strains. However, SW14 did not affect bacterial growth in standard microbiological broth or minimal medium that mimics the phagosomal environment. Cellular autophagy blockade by 3-methyladenine (3-MA) or shATG7 elevated the susceptibility of intracellular Salmonella to SW14. Finally, reactive oxygen species (ROS) scavengers reduced the antibacterial efficacy of SW14, but the ROS levels in SW14-treated macrophages were not elevated. SW14 decreased the resistance of outer membrane-compromised S. Typhimurium to H2O2. Collectively, our data indicated that the structure of loxapine can be further optimized to develop new antibacterial agents by targeting bacterial resistance to host oxidative-stress defense. IMPORTANCE The incidence of diseases caused by pathogenic bacteria with resistance to common antibiotics is consistently increasing. In addition, Gram-negative bacteria are particularly difficult to treat with antibiotics, especially those that can invade and proliferate intracellularly. In order to find a new antibacterial compound against intracellular Salmonella, we established a cell-based high-content assay and identified SW14 from the derivatives of the antipsychotic drug loxapine. Our data indicate that SW14 has no effect on free bacteria in the medium but can suppress the intracellular proliferation of multidrug-resistant (MDR) S. Typhimurium in macrophages. We also found that SW14 can suppress the resistance of outer membrane compromised Salmonella to H2O2, and its anti-intracellular Salmonella activity can be reversed by reactive oxygen species (ROS) scavengers. Together, the findings suggest that SW14 might act via a virulence-targeted mechanism and that its structure has the potential to be further developed as a new therapeutic against MDR Salmonella.

Effect of Novel Antipsychotics on Energy Metabolism - In Vitro Study in Pig Brain Mitochondria.

The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

Beneficial effects of loxapine on agitation and breathing patterns during weaning from mechanical ventilation.

INTRODUCTION: Interruption of sedation during weaning from mechanical ventilation often leads to patient agitation because of withdrawal syndrome. We tested the short-term efficacy and tolerance of loxapine in this situation. METHODS: Nineteen mechanically ventilated patients with marked agitation after sedation withdrawal were included. Three agitation scales, the Richmond Agitation Sedation Scale (RASS), the Motor Activity Assessment Scale (MAAS), and the Ramsay and physiological variables (respiratory rate, airway occlusion pressure during the first 0.1 second of inspiration (P0.1), heart rate and systolic arterial blood pressure) were recorded before and after loxapine administration. RESULTS: Loxapine dramatically improved all agitation scores (RASS and MASS decreased from 2 +/- 0 to -1.1 +/- 2.3, and 5.4 +/- 0.5 to 2.7 +/- 1.6, respectively; Ramsay increased from 1.0 +/- 0 to 3.5 +/- 1.5, 60 minutes after loxapine administration, P < 0.05 for all scores) as well as P0.1 (6 +/- 4.2 to 1.8 +/- 1.8 cm H2O; P < 0.05) and respiratory rate (from 31.2 +/- 7.2 to 23.4 +/- 7.8; P < 0.05) without hemodynamic adverse events. No side effects occurred. Sixteen (84%) patients were successfully managed with loxapine, sedation was resumed in two others, and one patient self-extubated without having to be reintubated. CONCLUSIONS: Loxapine was safe and effective in treating agitation in a small group of mechanically ventilated patients and improved respiratory physiologic parameters, enabling the weaning process to be pursued. A multicenter trial is under way to confirm these promising results.

Loxapine, an antipsychotic drug, suppresses intracellular multiple-antibiotic-resistant Salmonella enterica serovar Typhimurium in macrophages.

BACKGROUND: The emergence of multiple-antibiotic-resistant (MAR) Salmonella has been a serious threat worldwide. Salmonella can invade into host cells and evade the attacks of host humoral defenses and antibiotics. Thus, a new antibacterial agent capable of inhibiting intracellular Salmonella is highly needed. METHODS: The anti-intracellular activity and cytotoxicity of drugs on intracellular bacteria and macrophages were assayed using intracellular CFU assay and MTT cell viability assay, respectively. The uptake of gentamicin into macrophage and the effect of autophagy inhibitor on loxapine's anti-intracellular Salmonella activity were assessed by using image-based high-content system. The expression of bacterial genes was measured by real-time PCR. The efflux pump activity of bacteria was measured by Hoechst accumulation assays. RESULTS: With our efforts, an antipsychotic drug, loxapine, was identified to exhibit high potency in suppressing intracellular MAR S. Typhimurium, Staphylococcus aureus, Shigella flexneri or Yersinia enterocolitica. Subsequent investigations indicated that loxapine's anti-intracellular bacteria activity was not associated with increased penetration of gentamicin into bacteria and macrophages. Loxapine didn't inhibit bacterial growth in broth at concentration up to 500 µM and has no effect on Salmonella's type III secretion system genes' expression. Blockage of autophagy also didn't reverse loxapine's anti-intracellular activity. Lastly, loxapine suppressed bacterial efflux pump activity in all bacteria tested. CONCLUSION: Altogether, our data suggested that loxapine might suppress intracellular bacteria through inhibiting of bacterial efflux pumps. In light of its unique activity, loxapine represents a promising lead compound with translational potential for the development of a new antibacterial agent against intracellular bacteria.

Contrasting loxapine to its isomer isoloxapine--the critical role of in vivo D2 blockade in determining atypicality.

BACKGROUND: Loxapine is a typical antipsychotic while isoloxapine, its 8Cl-isomer, shows atypicality in some animal models. The basis for this difference is not well understood. The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles. METHODS: The in vitro and in vivo receptor profiles as well as the action of loxapine and isoloxapine on rat conditioned avoidance response (CAR), catalepsy (CAT), striatal FOS expression and prolactin levels were determined. To understand loxapine's typical profile, we added MDL100,907, to provide loxapine+MDL the same in vivo 5-HT2/D2 ratio as isoloxapine, while holding its D2 component constant. RESULTS: Isoloxapine behaved as an "atypical" antipsychotic demonstrating CAR inhibition, low CAT, no significant prolactin elevation, and minimal FOS expression in the dorsolateral striatum. Loxapine behaved like a typical antipsychotic, showing unexpectedly high in vivo D2 occupancy. Addition of MDL100,907, which resulted in a very high 5-HT2/D2 in vivo ratio, did not alter loxapine + MDL's typical profile. CONCLUSIONS: Loxapine's behaviour as a typical antipsychotic is most likely due to its disproportionately high D2 occupancy. Appropriate action at D2 receptors in vivo, rather than the high 5-HT2/D2 ratio, seems to be critical in determining why isoloxapine behaves like an atypical antipsychotic.

Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures.

The cytokines IL-1beta and IL-2 are released from activated glial cells in the central nervous system and they are able to enhance catecholaminergic neurotransmission. There is no data concerning influence of antipsychotics on glial cell activity. Antipsychotics reaching the brain act not only on neurons but probably also on glial cells. The aim of this study was to evaluate the effect of chlorpromazine and loxapine on release of IL-1beta and IL-2 by mixed glial and microglial cell cultures. Chlorpromazine in concentrations 2 and 20 muM, and loxapine 0.2, 2 and 20 microM reduced IL-1beta secretion by LPS-activated mixed glia cultures after 1 and 3 days of exposure. Chlorpromazine in concentrations of 0.2, 2 and 20 microM reduced the IL-2 secretion in mixed glial cultures after 3 days of exposure. Loxapine in concentrations of 0.2, 2 and 20 microM reduced IL-2 secretion in mixed glia cultures after 1 and 3 days of exposure, and additionally loxapine decreased IL-1beta and IL-2 secretion in LPS-induced microglia cultures in concentrations of 2, 10 and 20 muM. Quinpirole-a D2 dopaminergic agonist increased LPS-induced IL-1beta and IL-2 secretion in mixed glia cultures only in the highest dose of 20 microM. These findings suggest the absence of functional dopamine receptors on cortical microglial cells. Mixed glia cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester) did not release IL-1beta and IL-2. This observation suggests that microglia can be a source of assessed cytokines. Results of the present study support the view that antipsychotics act not only on neurons but also on glial cells. However, the clinical significance of these observations still remains unclear.

Atypical and typical antipsychotic drug interactions with the dopamine D2 receptor.

A model of the dopamine D2 receptor was used to study the receptor interactions of dopamine, the typical antipsychotics haloperidol and loxapine, and the atypical antipsychotics clozapine and melperone. The atypical antipsychotics interacted with the halogen atom of the ring system in the direction of the transmembrane helices (TMHs) 2, 3 and 7, while the typical had the corresponding halogen atom in the direction of TMH5. Molecular dynamics simulations indicated that the average helical displacement upon binding increased in the order: typical < atypical < dopamine. Upon binding, the atypical induced larger displacements into TMH5 than did the typical. The typical had stronger non-bonded interactions with the receptor than had the atypical, which is in agreement with the experimental observation that the atypical antipsychotic drugs dissociate faster from the receptor than the typical antipsychotic drugs.

Amoxapine: neuroleptic as well as antidepressant?

Amoxapine, a new antidepressant, is the N-desmethyl analog of loxapine, a neuroleptic. There have been reports suggesting that amoxapine itself or its metabolites have neuroleptic as well as antidepressant properties. With in vitro studies using a radioreceptor assay for neuroleptics, the authors found that amoxapine--and one of its metabolites in particular (7-hydroxyamoxapine)--have potent neuroleptic-like activity. Furthermore, blood specimens from patients receiving amoxapine showed the presence of neuroleptic activity in the same assay. The authors note the implications of these findings for gauging the benefits and risks of treatment with amoxapine, including the risk of neurologic effects.

PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.

OBJECTIVE: Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses. METHOD: Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively. RESULTS: The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors. CONCLUSIONS: Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

The interactions of typical and atypical antipsychotics with the (-)2, 5,-dimethoxy-4-methamphetamine (DOM) discriminative stimulus.

The present study was designed to test the hypothesis that atypical, but not typical, antipsychotics produce a functional in vivo blockade of 5-HT2A receptors. The magnitude of functional in vivo 5-HT2A receptor blockade elicited by representative compounds from each of the six major structural classes of typical antipsychotics, and the representative atypical antipsychotics clozapine and risperidone, was indicated by their respective abilities to block the stimulus effects of the phenylalkylamine hallucinogen (-)DOM in the rat. Chlorpromazine, thioridazine, fluphenazine, thiothixene and haloperidol did not produce a significant antagonism of the (-)DOM stimulus. The benzoxapine, loxapine (60%), and the atypical dibenzodiazepine, clozapine (62%), partially blocked and risperidone fully blocked (100%) the (-)DOM stimulus. None of these agents elicited significant levels of (-)DOM-appropriate responding when administered alone. These results indicate that the typical antipsychotics, with the exception of lozapine, fail to produce effective in vivo antagonism of 5-HT2A receptors at doses compatible with the preservation of operant behavior. In contrast, the atypical antipsychotics clozapine and risperidone elicit effective in vivo antagonism of 5-HT2A receptors without severe behavioral disruption. Thus, these data are supportive of the hypothesis that the mechanism of action of atypical, but not typical, antipsychotics involves the antagonism of 5-HT2A receptors in vivo.

Drug interactions on spontaneous locomotor activity in rats. Neuroleptics and amphetamine-induced hyperactivity.

The locomotor activity of female rats was recorded during 10-min sessions in a circular open-field apparatus after the administration of vehicle or drug. Dose-response curves were obtained for seven neuroleptic drugs both alone (spontaneous activity) and in combination with 1.0 mg/kg of d-amphetamine. Haloperidol, pimozide, loxapine, thiothixene, molindone and chlorpromazine all produced graded decreases in spontaneous locomotor activity. Haloperidol, pimozide, loxapine, thiothixene and molindone also produced graded reversals of the hyperactivity produced by d-amphetamine, while chlorpromazine did not. Clozapine neither altered spontaneous activity nor reversed the hyperactivity produced by d-amphetamine. The data indicate that measures of locomotor activity provide important additional information about the actions of neuroleptics and do not necessarily mirror the actions of these drugs on other measures of performance such as lever-pressing for brain stimulation.

Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent.

Loxapine is a dibenzoxazepine, tricyclic compound recommended for the treatment of acute and chronic schizophrenia. In its therapeutic effectiveness and profile and incidence of side-effects, loxapine closely resembles the traditional antipsychotic agents. Although loxapine has tended to be less effective than some standard antipsychotic drugs in a few short-term (3 to 4 weeks) studies, it has been superior to a placebo and about as effective as chlorpromazine, haloperidol, trifluoperazine or thiothixene when evaluated after 4 to 12 weeks. Like the phenothiazine (e.g. chlorpromazine) and butyrophenone (e.g. haloperidol) antipsychotic agents, loxapine causes a high incidence of extrapyramidal reactions. Sedation occurs frequently, especially during early stages of treatment. Other, less common side-effects such as anticholinergic effects (dry mouth, blurred vision, etc.), hypotension, tachycardia and precipitation of epileptic seizures, which occur with the older antipsychotic drugs, have also been reported with loxapine.

Binding of psychotropic drugs to isolated alpha-acid glycoprotein.

Alpha1-acid glycoprotein (alpha1-AG) was purified from human sera, and its binding properties with respect to psychotropic drugs were examined by equilibrium dialysis methods in order to clarify the specificity of binding. Radioactive imipramine, a tricyclic antidepressant, was used as the primary ligand. Other drugs, representative of different classes, were tested as potential inhibitors of the alpha1-AG-imipramine binding. The K(a) for imipramine was 2.8 x 10(5) (+/- 0.8) M(-10 (mean +/- S.D.). Chlorpromazine, fluphenazine, thioridazine, loxapine and thiothixene, which are antipsychotic drugs, were competitive inhibitors of imipramine binding, and their K(a) values were in the same range. Propranolol, haloperidol and diazepam were also competitive inhibitors but their affinities were lower. Molindone, an indolic antipsychotic, when tested at the same concentrations as the other drugs, did not affect imipramine binding. Trihexyphenidyl, an anti-Parkinson drug, was a potent but noncompetitive inhibitor. These data identify the antidepressant and major tranquilizer drugs that exhibit high affinity for alpha1-AG and indicate that alpha1-AG may account for 40 per cent of total imipramine bound in serum. Since in psychiatric clinical practice two drugs are frequently administered together, possible competitive effects are discussed as well as the potential role of alpha1-AG in psychiatric illness.

The effect of antipsychotic drugs on body weight: a retrospective review.

Weight gain in schizophrenic patients during chemotherapy was first reported with chlorpromazine. Since then other antipsychotic drugs have exhibited this effect, while some have reduced weight. A retrospective review of 78 schizophrenic patients revealed that thiothixene, fluphenazine, haloperidol, and thioridazine produced a mean weight gain and loxapine a mean weight loss after 12 and 36 weeks of treatment. The ability of an effective antipsychotic drug, such as loxapine, to prevent weight gain or to produce weight loss offers a clinical advantage in the treatment of those schizophrenic patients where weight gain should be a problem.

A comparison of parenteral loxapine and haloperidol in hostile and aggressive acutely schizophrenic patients.

In a parallel groups, double-blind study, 54 acutely psychotic schizophrenics were given loxapine or haloperidol parenterally for 24 to 72 hours, then orally for a total study period of up to 10 days. Dosage ratios of loxapine to haloperidol ranged from a minimum of 2.7:1 to a maximum of 4.4:1. Both groups showed significant and rapid improvement from baseline. Forty-eight percent of the loxapine patients and 33% of the haloperidol patients achieved and maintained a global severity of illness rating of mild or better. By the end of the study, 84% of the loxapine patients and 63% of the haloperidol patients had achieved an improvement rating of moderate or marked. This difference approached significance (p less than .10). The most frequently reported adverse experiences were dystonic reactions and akathisia. The number and severity of adverse experiences did not differ significantly between drug groups. Intramuscular loxapine was at least as effective as haloperidol in the initial management of hostile and aggressive schizophrenic patients. The maintenance of therapeutic response after conversion to oral concentrate was comparable with the two drugs.