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The field of food allergy has seen tremendous change over the past 5-10 years with seminal studies redefining our approach to prevention and management and novel testing modalities in the horizon. Early introduction of allergenic foods is now recommended, challenging the previous paradigm of restrictive avoidance. The management of food allergy has shifted from a passive avoidance approach to active interventions that aim to provide protection from accidental exposures, decrease allergic reaction severity and improve the quality of life of food-allergic patients and their families. Additionally, novel diagnostic tools are making their way into the clinical practice with the goal to reduce the need for food challenges and assist physicians in the – often complex – diagnostic process. With all the new developments and available choices for diagnosis, prevention and therapy, shared decision-making has become a key part of the medical consultation, enabling patients to make the right choice for them, based on their values and preferences. Communication with patients has also become more complex over time, as patients are seeking advice online and through social media, but the information found online may be outdated, incorrect, or lacking in context. The role of the allergist has evolved to embrace all the above exciting developments and provide patients with the optimal care that fits their needs. In this review, we discuss recent developments, as well as the evolution of the field of food allergy in the next decade.

Objective This study examined the relationship between severity of illicit substance use at the time of study entry in a sample of patients diagnosed with schizophrenia and 18-month longitudinal outcomes, including psychopathology, depression, neurocognition, and quality of life. Methods Subjects in the Clinical Antipsychotic Trials of Intervention Effectiveness (N = 1432) were divided into three groups according to baseline data: (1) those with moderate/severe drug use, (2) those with mild drug use, and (3) non-users of illicit substances. The groups were compared on other baseline characteristics. Mixed model analysis was used to compare outcomes between the groups using all available outcome data over 18 months, controlling for potential confounding baseline characteristics. Least square means were compared between pairs of groups in the mixed models. Results Significantly poorer outcomes were observed in the domains of psychosis, symptoms of depression, and quality of life for moderate/severe drug users in comparison with both mild users and abstainers. No significant differences were found on neurocognitive functioning or days of employment. Conclusions This study suggests that drug use-related impairment co-morbid with schizophrenia may not be a function of use per se but rather, of the severity of use. It highlights the importance of comprehensive assessment and treatment of illicit substance abuse in schizophrenia. Long-term treatment approaches that integrate harm reduction strategies may offer promise in maximizing positive outcomes for such dually diagnosed patients.

We evaluated the consequences of heterozygous chromosome 22q11 deletion – a significant genetic risk for schizophrenia – for expression levels and patterns of a subset of 22q11 genes implicated in schizophrenia and other phenotypes in mouse models of 22q11 deletion syndrome (22q11DS). In deleted embryos, expression levels of at least nine 22q11 orthologues decline by 40–60% in the frontonasal mass/forebrain and other 22q11DS phenotypic sites (branchial and aortic arches, limb buds); however, coincident expression patterns of 22q11 and Snail genes – diagnostic for neural crest-derived mesenchyme – are unchanged, and Snail1 expression levels do not decline. Subsequently, 22q11 mRNA levels are reduced by 40–60% in the brains of developing, adolescent and adult deleted mice without altered expression patterns, dysmorphology or reduced cell density. Apparently, in deleted individuals, 22q11 gene expression declines across otherwise stable cell populations, perhaps disrupting individual cell function via diminished dosage. Such changes might contribute to schizophrenia vulnerability in 22q11DS.

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.

The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for TD which is in part attributed to their ability to block the serotonin-2A (5-HT2A) receptor. 5-HT2A receptors were also identified in the basal ganglia; a brain region that plays a critical role in antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT2A receptor gene (HTR2A) in relation to the TD phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal Involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated. In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.

Subanesthetic doses of NMDA receptor antagonists induce positive, negative and cognitive schizophrenia-like symptoms in healthy humans and precipitate psychotic reactions in stabilized schizophrenic patients. These findings suggest that defining neurobiologic effects induced by NMDA antagonists could guide the formulation of experimental models relevant to the pathophysiology of schizophrenia and antipsychotic drug action. Accordingly, the effects of subanesthetic doses of the non-competitive NMDA antagonists ketamine and MK-801 were examined on regional brain [14C]-2-deoxyglucose (2-DG) uptake in rats. The effects of these drugs were compared to those of amphetamine, in order to assess the potential role of generalized behavioral arousal, motor activity and dopamine release in brain metabolic responses to the NMDA antagonists. Subanesthetic doses of MK-801 and ketamine induced identical alterations in patterns of 2-DG uptake. The most pronounced increases in 2-DG for both NMDA antagonists were in the hippocampal formation and limbic cortical regions. By contrast, amphetamine treatment did not increase 2-DG uptake in these regions. In isocortical regions, ketamine and MK-801 reduced uptake in layers 3 and 4, creating a striking shift in the laminar pattern of 2-DG uptake in comparison to control conditions. After amphetamine, the fundamental laminar pattern of isocortical labeling was similar to saline-treated rats. Administration of ketamine and MK-801 decreased 2-DG uptake in the medial geniculate and inferior colliculus, whereas amphetamine tended to increase uptake in these regions. Since ketamine induced similar effects on regional 2-DG uptake as observed for the selective antagonists MK-801, the effects of ketamine are likely related to NMDA antagonistic properties of the drug. The distinct differences in brain 2-DG uptake induced by amphetamine and NMDA antagonists indicate that generalized behavioral arousal, and increased locomotor activity mediated by dopamine release, are not sufficient to account for the alterations in brain metabolic patterns induced by ketamine and MK-801. Thus, the dramatic alteration in regional 2-DG uptake induced by ketamine and MK-801 reflects a state selectively induced by reduced NMDA receptor function.

BackgroundConverging evidence has suggested that the abnormalities in brain morphology observed in schizophrenia are similar to those seen in temporal lobe epilepsy (TLE). The purpose ofthis study was to compare the features of these groups directly with measures of the brain using magnetic resonance (MR) morphometry.MethodMorphometric measures of ventricular and hippocampal volumes obtained from FLASH MR images were studied in 32 patients with first-episode schizophrenia (FES), 39 patients withTLE (21 left, 18 right), and 42 healthy controls.ResultsVentricular volumes in the FES and TLE groups were both significantly larger than those seen in controls and did not differ from each other. The FES group showed significantly larger temporal horns, while theTLE group had relatively larger frontal horns. Analyses of hippocampal volumes revealed a significant group by hemisphere effect. The FES group showed relative reductions in left hippocampal volume that were comparable only toTLE patients with seizures originating from the left hemisphere.ConclusionThe results indicate that FES and TLE groups both show evidence of ventricular enlargement. Lateralised morphological abnormalities of the hippocampal formation in FES and left TLE are comparable, and may be specific to temporolimbic regions.

Objective This study sought to elucidate the relation of clinical, neuropsychological, and seizure variables to chronic and postictal psychoses in patients with temporal lobe epilepsy. Method Forty-four patients with treatment-refractory temporal lobe epilepsy were given formal psychiatric evaluations; 29 patients had no psychiatric disorder or a nonpsychotic disorder, eight patients had postictal psychoses, and seven patients had chronic psychoses. Comparisons of clinical, neuropsychological, magnetic resonance imaging, and seizure variables were made between the nonpsychotic and the psychotic patients and, secondarily, between the patients with transient postictal psychoses and those with chronic psychoses. Results Bitemporal seizure foci, clustering of seizures, and absence of febrile convulsions were associated with both postictal psychoses and chronic psychoses. Younger age at onset of epilepsy and lower verbal and full-scale IQs differentiated the patients with chronic psychoses from those with postictal psychoses. Conclusions Patients with temporal lobe epilepsy with chronic and postictal psychoses show similar profiles of clinical and seizure variables, suggesting shared etiologic factors. These factors may increase the propensity to develop psychotic symptoms, while other factors, such as time of onset of epilepsy and underlying neuropathology, may determine whether transient or chronic psychotic symptoms develop. Even among patients with treatment-refractory temporal lobe epilepsy, a specific subgroup of patients, characterized by bitemporal seizure foci, an absence of febrile convulsions, and a history of clustering of seizures, appears to be particularly prone to develop psychotic disorders. A process similar to secondary epileptogenesis may be involved in the development of the psychoses.

Objective: The goal ofthis study was to determine whether patients experiencing their first episode ofschizophrenia differ from healthy subjects in regional cerebral hemispheric volumes or asymmetries. Method: Regional volumes corresponding to prefrontal, premotor, sensorimotor, occipitoparietal, and temporal lobes in each hemisphere were measured on contiguous coronal magnetic resonance images in 70 patients experiencing their first episode of schizophrenia and in 51 healthy comparison subjects. Results: Patients did not differ from the cornparison subjects in regional or total hemispheric volumes, but they had abnormal hemispheric asymmetries. Subjects in the comparison group had significant lateral asymmetries in each region: their occipitoparietal and sensorimotor regions were larger on the left, and their premotor, prefrontal, and temporal regions were larger on the right. Patients lacked lateral asymmetries and showed significantly less asymmetry than healthy subjects in occipitoparietal, premotor, and prefrontal regions. Absence of the normal asymmetry was more common among patients initially diagnosed with the undifferentiated than with the paranoid subtype ofschizophrenia and was associated with more severe negative symptoms among men. Asymmetries were related to sex and handedness regardless of diagnosis; specifically, dextral men showed more asymmetry than nondextral men or dextral women. Conclusions: The absence of normal hemispheric asymmetries suggests an anomaly in the development oflaterally specialized cerebral systems in schizophrenia, and this may be associated with an initial presentation of nonparanoid psychosis. (AmJ Psychiatry 1994; 151:1437-1447)

Objective: The prevalence, clinical correlates, and outcome of the deficit syndrome were determined for 70 patients ascertained in their first episode of schizophrenia and then followed through their recovery. Method: Patients were treated in a standardized manner and underwent baseline assessments ofsymptoms and adverse effects that were repeated at intervals throughout their inpatient and subsequent outpatient course. Forty-seven patients were followed for a minimum of6 months after remission oftheir positive symptoms, allowing for an assessment of their deficit syndrome status. Results: Using modified criteria of Carpenter et al. for the deficit syndrome, the authors found that two patients (4%) met all criteria for the deficit syndrome, nine (1 9%) had deficit symptoms (questionable deficit state), and 36 (77%) had no deficit symptoms. When patients who had not fully remitted or had remitted for less than 6 months were included, seven (10%) met deficit syndrome criteria, 1 1 (16%) had deficit symptoms, and 52 (74%) had no deficit symptoms. Conclusions: The prevalence ofthe deficit syndrome in first-episode schizophrenia varies depending on the criteria used and is lower than that previously described in more chronic patient samples. Patients without deficit symptoms had better premorbid functioning and a better global outcome than patients with deficit symptoms. (AmJ Psychiatry 1994; 151:1417-1422)

Objective This study examined the pathomorphology of the caudate nuclei in first-episode schizophrenic patients with minimal previous neuroleptic exposure. Method Magnetic resonance imaging (MRI) of the brain was used to examine longitudinally the caudate pathomorphology in 29 first-episode schizophrenic patients and 10 healthy comparison subjects. MRI scans were obtained after the subjects entered the study and at 18-month follow-up. The patients were treated with standardized neuroleptic regimens during the 18-month period. Volumetric assessments of the cerebral cortex, lateral ventricles, and caudate nuclei were performed on T1-weighted coronal brain sections. In addition, the patients were systematically evaluated for psychopathology at baseline and during treatment. Results Caudate volumes increased 5.7% in the patients during the 18-month treatment interval, whereas they decreased 1.6% in the comparison subjects over the same time period. Greater amounts of antipsychotic medication received by patients before the first scan and younger age at the time of the first scan were associated with larger increases in caudate volume. Conclusions Caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.

Six genes in the 1.5 Mb region of chromosome 22 deleted in DiGeorge/22q11 deletion syndrome-Mrpl40, Prodh, Slc25a1, Txnrd2, T10, and Zdhhc8-encode mitochondrial proteins. All six genes are expressed in the brain, and maximal expression coincides with peak forebrain synaptogenesis shortly after birth. Furthermore, their protein products are associated with brain mitochondria, including those in synaptic terminals. Among the six, only Zddhc8 influences mitochondria-regulated apoptosis when overexpressed, and appears to interact biochemically with established mitochondrial proteins. Zdhhc8 has an apparent interaction with Uqcrc1, a component of mitochondrial complex III. The two proteins are coincidently expressed in pre-synaptic processes; however, Zdhhc8 is more frequently seen in glutamatergic terminals. 22q11 deletion may alter metabolic properties of cortical mitochondria during early post-natal life, since expression complex III components, including Uqcrc1, is significantly increased at birth in a mouse model of 22q11 deletion, and declines to normal values in adulthood. Our results suggest that altered dosage of one, or several 22q11 mitochondrial genes, particularly during early post-natal cortical development, may disrupt neuronal metabolism or synaptic signaling.

Cortical neurosteroid levels vary dramatically across development; during the second week of life elevated levels of allopregnanolone are associated with decreased GABA(A) receptor function. Since GABA(A) receptor modulation plays a role in proliferative regulation in developing neocortex, it is possible that endogenous neurosteroids such as allopregnanolone, acting through GABA(A) receptors, modulate cortical development. We augmented normally low levels with exogenous administration of allopregnanolone (10 mg/kg) during the first week of rodent life. The localization of parvalbumin-labeled cells was markedly altered; the ratio of cell number in the deep (layers V-VI) vs. superficial (layers I-III) layers of adult prefrontal cortex increased two-fold in rats administered allopregnanolone on postnatal day 1 or 5. The mechanism underlying these anatomical changes likely involves GABA(A) receptors because similar changes in interneuron placement were observed after neonatal benzodiazepine administration. Measures of mature cortical function were also altered after neonatal neurosteroid administration, including [(3)H]MK-801 binding, prepulse inhibition and amphetamine-induced locomotor activity. Moreover, neonatal allopregnanolone administration increases the number of parvalbumin-expressing neurons in medial dorsal nucleus of the thalamus while the total neuron number is decreased. These findings suggest that connectivity between the medial dorsal nucleus of the thalamus and prefrontal cortex is likely altered by neonatal neurosteroid administration and may result in a disinhibited frontal cortex. Disinhibition in the prefrontal cortex is associated with behavioral changes relevant to human psychosis and developmental disorders. If neurosteroids play a role in normal development of prefrontal/medial dorsal patency as suggested by these studies, then alterations in neurosteroid levels may contribute to abnormal neurodevelopment.

Reduced N-methyl D-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle.The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1-/-) mice would be affected by antipsychotic drug treatment.Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli.Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1-/- mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1-/- or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice.The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.

With increasing numbers of treatment options available for patients with major depression over the last decade and the growing body of evidence describing their efficacy and safety, clinicians often find it difficult to determine the best and most appropriate evidence-based treatment for each patient. Systematic reviews utilizing statistical methods that synthesize and evaluate data from a number of studies have become increasingly more available over the past decade. We review major findings and lessons learned from salient examples of quantitative analyses of antidepressant research and provide recommendations for meta-analysts, journal and grant reviewers, and research 'consumers' (ie, clinicians) for conducting, reporting, and evaluating such analyses.

Fast-scan cyclic voltammetry in brain slices and postmortem tissue content assessment were used to evaluate presynaptic dopaminergic function in the caudate putamen and nucleus accumbens of adult male rats (180+ days old) that were prenatally treated with either cocaine or saline. Experiments were carried out to test whether there were differences in dopamine release, reuptake, autoreceptor function or the tissue levels of dopamine and its metabolites between cocaine- and saline-exposed rats. We report that presynaptic dopaminergic function remains largely intact in adult rats that were prenatally exposed to cocaine. The ability of terminals in the caudate putamen and nucleus accumbens to release and regulate dopamine is unaltered by prenatal cocaine exposure. However the tissue content of dopamine in the caudate putamen was decreased, representing a diminution in the dopamine storage pool. We conclude, therefore, that behavioral changes that have previously been observed in rats that were prenatally exposed to cocaine are not mediated through alteration of presynaptic dopaminergic mechanisms in these brain regions.

Dopamine supersensitivity, presumably playing a role in tardive dyskinesia, has been implicated in the unexplained polydipsia occurring in chronic psychiatric patients. To investigate this hypothesis, the authors compared laboratory measurements indicating the fluid status of 65 patients before and after the development of tardive dyskinesia. No evidence was found that patients who develop tardive dyskinesia concurrently develop abnormalities in fluid regulation.

Diabetes mellitus has been identified as a possible risk factor for tardive dyskinesia. The authors examined 160 elderly individuals who were beginning neuroleptic treatment; 24 had diabetes and 136 did not. After 43 weeks of neuroleptic exposure, the cumulative incidence rates of tardive dyskinesia were 54.1% (SE = 5.6%) for the diabetics and 25.6% (SE = 16.1%) for the nondiabetics.

Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.

A number of consistent clinical observations provide direction for the hypothesis that pathological sensitization of neuronal systems may be an important factor for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and schizophrenia. First, psychotic symptoms can be produced in normal subjects by stimulants. Secondly, a large portion of schizophrenic patients exhibit exacerbation of psychotic symptoms in response to stimulants at doses which would not be psychotogenic in normal subjects. Lastly, the ability of stress to precipitate the onset and relapse of schizophrenia is well documented. In this regard, acute responses to stimulants provide useful information for relapse prediction of schizophrenia and substance abuse. This paper addresses the nature and role of pathological sensitization in relapse of stimulant- and phencyclidine-induced psychosis and schizophrenia, and its relation to pathophysiology of schizophrenia.

Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.

Pathophysiological processes that underlie the profound neuropsychiatric disturbances in schizophrenia are poorly understood. However, the clinical course of the disease, and a number of clinical and basic science observations, provide direction for formulating pathophysiological models that could be empirically tested. For example, repeated psychostimulant administration to healthy subjects can induce psychotic symptoms, and acute stimulant challenge in schizophrenia patients can precipitate psychosis. Also, NMDA antagonists induce positive, negative, and cognitive schizophrenic-like symptoms in healthy volunteers and precipitate thought disorder and delusions in schizophrenia patients. These human studies provide support for the dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Well-documented effects of NMDA antagonists on dopamine systems provide a basis to integrate the dopamine and NMDA receptor hypofunction hypotheses. Furthermore, it has become apparent that prominent actions of antipsychotic drugs, especially those with `atypical' properties, involve antagonism of behavioral, electrophysiological and brain metabolic effects produced by administration of NMDA receptor antagonists. A confluence of clinical and basic science data suggests that an early developmental insult, potentially involving reduced NMDA receptor function, could facilitate sensitization of dopamine systems, leading to the formal onset of schizophrenia in late adolescence and early adulthood. Although clearly speculative, this conceptual model is consistent with existing evidence and suggests lines of future experimental investigation.

It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis. Hence, the authors examined patients with first-episode psychosis to determine the efficacy and safety of olanzapine and haloperidol treatment.A subpopulation of first-episode patients (N=83) from a large prospective, multicenter, international, double-blind, 6-week acute treatment study was evaluated. These patients were selected from a pool of 1,996 patients who had a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder and who also met the following criteria: 1) the length of their current psychotic episode had to be 5 or fewer years, and 2) patients had to be 45 years of age or younger at onset of first psychotic symptoms.Compared to haloperidol, olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) total and negative scores and in the Positive and Negative Syndrome Scale total and positive scores. Clinical response (defined as 40% or greater improvement in BPRS total score from baseline) was also statistically significantly higher in olanzapine-treated patients (67.2%) than in haloperidol-treated patients (29.2%). Olanzapine-treated patients further showed statistically significant improvements in the Simpson-Angus scale and Barnes Akathisia Scale scores, while haloperidol-treated patients showed a worsening on both measures. Compared to olanzapine-treated multiple-episode patients in the parent study, olanzapine-treated first-episode patients achieved an even statistically significantly higher response. Haloperidol-treated first-episode patients experienced statistically significantly more extrapyramidal symptoms than haloperidol-treated multiple-episode patients.In patients experiencing first-episode psychosis, olanzapine had a risk-benefit profile significantly superior to that of haloperidol. The study results suggest that novel antipsychotic agents such as olanzapine should be considered as a preferred option in first-episode psychosis, on the basis of both safety and efficacy advantages.

Subanesthetic doses of N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine and phencyclidine precipitate psychotic symptoms in schizophrenic patients. In addition, these drugs induce a constellation of behavioral effects in healthy individuals that resemble positive, negative, and cognitive symptoms of schizophrenia. Such findings have led to the hypothesis that decreases in function mediated by NMDA receptors may be a predisposing, or even causative, factor in schizophrenia. The present study examined the effects of the representative atypical (clozapine) and typical (haloperidol) antipsychotic drugs on ketamine- induced increases in [14C]-2-deoxyglucose (2-DG) uptake in the rat brain. As previously demonstrated, administration of subanesthetic doses of ketamine increased 2-DG uptake in specific brain regions, including medial prefrontal cortex, retrosplenial cortex, hippocampus, nucleus accumbens, basolateral amygdala, and anterior ventral thalamic nucleus. Pretreatment of rats with 5 or 10 mg/kg clozapine alone produced minimal or no change in 2-DG uptake, yet clozapine completely blocked ketamine-induced changes in 2-DG uptake in all brain regions studied. In striking contrast, a dose of haloperidol (0.5 mg/kg) that produces a substantial cataleptic response, potentiated, rather than blocked, ketamine-induced activation of 2-DG uptake. These results demonstrate, in a model with potential relevance to schizophrenia, a striking neurobiological difference between the actions of prototypical typical and atypical antipsychotic drugs. The dramatic blockade by clozapine of ketamine-induced brain metabolic activation suggests that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior therapeutic effects of this atypical antipsychotic agent. The results also suggest that this model of ketamine-induced alterations in 2-DG uptake may be extremely useful for understanding the complex neural mechanisms of atypical antipsychotic drug action.

Defining treatment resistance among schizophrenia patients is problematic since most patients experience persistent morbidity over the course of their illness and full remissions are infrequent. In addition, the level of response to antipsychotic medication is not an immutable feature of the patient's illness that is present at its onset; rather, it can change over the course of the illness (usually unidirectionally with patients becoming less responsive to treatment) and is determined by various modifying factors. Although treatment resistance may be an enduring feature of a patient, present at illness onset and throughout, more commonly it develops over the course of patients' illnesses. Evidence from both retrospective and prospective studies suggests that a longer duration of untreated psychosis in the early stage of schizophrenia is associated with a longer time to remission and a lower level of recovery, a greater likelihood of relapse and a worse overall outcome. The pattern of deterioration observed is analogous to a well replicated neurobiologic phenomenon, termed behavioral sensitization. In sensitized animals a pathologic behavioral process emerges whereby the response to a pharmacologic or stress challenge is progressively increased in proportion to the number of pretreatments. Thus, endogenous neurochemical sensitization resulting from the inability to regulate presynaptic dopamine release in the limbic striatum may be a useful way to conceptualize the continuum of response-refractoriness that is clearly evident in schizophrenia patients. Most importantly, early detection, intervention and optimal maintenance treatment may improve the long term course of schizophrenia.

Objective : The authors evaluate the forces that are changing psychiatric practice and propose options for redefining the clinical and educational goals of psychiatry within medicine. Method : An overview of current external and internal forces shaping psychiatry is provided. These forces are both social, political, and economic (external) and scientific and technological (internal). Results : The convergence of these forces leads to recommendations for redefining psychiatric practice and education. If psychiatry fails to redefine itself on the basis of its scientific foundations, political and economic forces may lead to an untenable redefinition that could threaten the field. Conclusions : The redefinition process may lead to altered roles and somewhat different knowledge bases for psychiatry. The profession must choose whether to be reactive or proactive given this challenge.

We examined the response to clozapine in 10 schizophrenic patients who had been followed prospectively from the time of their first hospitalization and who were refractory to multiple clinical trials with typical neuroleptics

OBJECTIVE The aim of this study was to determine the relation between plasma fluphenazine levels and clinical response in first-episode schizophrenic patients. METHOD Data from 36 first-episode schizophrenic or schizoaffective inpatients diagnosed according to the Research Diagnostic Criteria were evaluated. The patients received open, standardized treatment with fluphenazine, 20 mg/day, for at least 4 weeks. Psychopathology was assessed biweekly, and plasma fluphenazine levels were ascertained weekly. Patients were classified as responders or nonresponders, and correlations between their neuroleptic levels and ratings of psychopathologic and extrapyramidal symptoms were computed. RESULTS Plasma fluphenazine levels for weeks 1 through 4 were significantly correlated with each other but were not correlated with age, gender, diagnosis, or race. Mean neuroleptic levels (weeks 3 and 4) were not different between responders and nonresponders and were not correlated with measures of psychopathology or extrapyramidal symptoms. CONCLUSIONS These results do not indicate an association between plasma fluphenazine levels and response to treatment or extrapyramidal side effects in first-episode schizophrenia. The disparity between the results of this study and those of previous studies may be due to methodological differences or to a biologically based difference between first-episode and chronic patients.

Ten schizophrenic patients and five normal control subjects were challenged with growth hormone-releasing hormone in a pilot study investigating growth hormone secretion from the pituitary. The results suggest suprapituitary dysfunction in schizophrenia, but replication in a larger study is needed.