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Background: Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns., Methods: This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3)., Results: Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders., Conclusions: Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

The cloning of the dopamine (DA) D2 receptor now permits the characterization and regulation of D2 messenger RNA (mRNA) in the brain. In this article, the authors describe their studies delineating the distribution of D2 receptor mRNA in the rodent and primate brain, and compare the distribution of message to D2 receptor binding sites. The effects of chronic DA agonist and antagonist treatment on D2 receptor mRNA are also presented, and provide insights into receptor regulation. Finally, the autoreceptor role of D2 receptors located in the midbrain is examined with a combination of 6-hydroxydopamine lesions and anatomic colocalization studies with tyrosine hydroxylase. These preclinical results provide a framework for subsequent investigation into the nature of D2 receptor gene expression in postmortem brains from patients with disorders putatively associated with dopaminergic dysfunction, especially schizophrenia. They also lay the groundwork for a more profound understanding of DA neurocircuitry by combining molecular biological and traditional anatomical techniques.

This paper is not a comprehensive review of the literature. Rather, it is a viewpoint based upon advances in other fields of medicine and genetics that may provide a model for guiding research in psychiatry. The paper discusses the major limitations of the medicines currently used to treat schizophrenia and bipolar illness. The limitations in our understanding of the molecular causes of these two illnesses and our lack of a clear mechanism of action for many of the medicines used to treat them continue to confound the field and impede progress towards finding novel treatments. Until the genetic bases of bipolar illness and schizophrenia are unambiguously identified, progress towards improved diagnosis and treatment will be retarded. An approach to identifying risk genes based upon association studies starting with very large sample sizes based upon currently available diagnoses of bipolar disorder and schizophrenia is advocated.

This paper reviews the evidence that antipsychotic drugs induce neuroplasticity. We outline how the synaptic changes induced by the antipsychotic drug haloperidol may help our understanding of the mechanism of action of antipsychotic drugs in general, and how they may help to elucidate the neurobiology of schizophrenia. Studies have provided compelling evidence that haloperidol induces anatomical and molecular changes in the striatum. Anatomical changes have been documented at the level of regional brain volume, synapse morphology, and synapse number. At the molecular level, haloperidol has been shown to cause phosphorylation of proteins and to induce gene expression. The molecular responses to conventional antipsychotic drugs are predominantly observed in the striatum and nucleus accumbens, whereas atypical antipsychotic drugs have a subtler and more widespread impact. We conclude that the ability of antipsychotic drugs to induce anatomical and molecular changes in the brain may be relevant for their antipsychotic properties. The delayed therapeutic action of antipsychotic drugs, together with their promotion of neuroplasticity suggests that modification of synaptic connections by antipsychotic drugs is important for their mode of action. The concept of schizophrenia as a disorder of synaptic organization will benefit from a better understanding of the synaptic changes induced by antipsychotic drugs.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

The present review explores the descriptive epidemiology of schizophrenia. Risk factors and correlates are divided into three groups based on whether the available evidence is consistent and strong, consistent and potentially strong, or inconsistent. The paper then considers epidemiologic studies of the course of illness, including a description of findings from the Suffolk County Mental Health Project. Given renewed attention to the need for preventive interventions for individuals at high risk for developing a psychotic illness, epidemiologic values have become more and more central to the conduct of clinical research.

Background: Psychosis is a defining feature of schizophrenia consisting of formal thought disorder, delusions, and hallucinations. Although psychosis is present in the majority of patients with schizophrenia, the prevalence, responsiveness to atypical antipsychotic drug therapy, and prediction of outcome of individual psychotic symptoms in a population of well-diagnosed patients with schizophrenia have not been conclusively established., Methods: This paper examined the prevalence, responsiveness to the atypical antipsychotic olanzapine, and relationship to outcome of individual psychotic symptoms using data from a previously reported large multicenter, double-blind clinical trial of olanzapine (mean daily dose at endpoint = 13.6 +/- 6.9 mg/day)., Results: The most frequently reported psychotic symptoms at baseline were delusions (65%), conceptual disorganization (50%), and hallucinations (52%), and the majority of patients (68%) experienced from one to three symptoms. Additionally, with olanzapine treatment there were significant improvements (p < .001) in baseline to endpoint Positive and Negative Symptom Scale (PANSS) psychotic item scores, with the largest effect sizes observed for hallucinatory behavior, unusual thought content, suspiciousness/persecution, and delusions. During the acute phase of the trial, quality of life was correlated significantly with baseline conceptual disorganization (p = .038) and unusual thought content (p = .023), and time spent in the hospital was correlated with unusual thought content (p = .005)., Conclusions: The implications of these for the clinical management of schizophrenia are discussed.

Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified., Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question., Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase., Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.

Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. There are two reasons for the new emphasis: the tremendous success of the so-called "atypical" antipsychotic drugs (a common feature of which is their high affinity for specific 5-HT receptor subtypes); and the elucidation of a complex family of 5-HT receptors whose function and pharmacology is only beginning to be understood. This paper will review the evidence that pertains to the role of 5-HT in mediating antipsychotic drug effects. The interaction of dopamine and 5-HT systems will be reviewed, and the mechanisms of action of atypical antipsychotic drugs will be evaluated in this context. The impact of serotonin on neurodevelopment, and the involvement of serotonin in the psychotomimetic and psychotogenic properties of hallucinogens, will be discussed. Together, these facts will be placed into the context of changes in serotonergic function in schizophrenia.

The aim of the present paper was to perform a single trial analysis of event-related potentials in order to elucidate the mechanisms behind a reduced P300 amplitude occurring in unmedicated depressives (n = 11) and schizophrenics (n = 18). For this purpose, tools from linear system theory were applied to single trials in an oddball paradigm. This analysis provides estimates of the magnitude of the positive deflection occurring around the latency of P300 following target and nontarget simuli. According to the density functions of these amplitude distributions, we operationally defined "false-negative" (P300 amplitude lower than an individual threshold under target conditions) as well as "false-positive" responses (P300 amplitude higher than the threshold following nontarget stimuli). Our investigations revealed a reduction of the single-trial P300 amplitude in depression and a combination of amplitude reduction along with fewer elicited single-trial P300 waves in schizophrenics.

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinson's disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

We have previously reported that prolactin (PRL) responses to haloperidol 0.5 mg IV were blunted in subjects characterized by several diagnostic systems of schizophrenia compared to controls (Keks et al 1990). However, an attempt to find a diagnostic system most different from controls was unsuccessful due to inherent difficulties in the statistical analysis of multidiagnostic data. In this paper we present new methodologies. A test for differences in dependent correlations demonstrated that most of the variance in stimulated PRL was accounted for by Kraepelinian, and least by Schneiderian and M. Bleulerian, schizophrenias (p < 0.001). The main symptomatic difference between nonKraepelinian and Kraepelinian patients was the presence of association disturbance and feelings of passivity. Patients with both symptoms had a lower stimulated PRL than controls. Further findings and possible implications are discussed.

We and others have shown that in vitro tryptoline (tetrahydro-beta-carboline) formation accounts for the apparent-N-methylating activity of a brain enzymatic preparation using 5-methyltetrahydrofolic acid (5-MTHF) as a cofactor and tryptamines or catecholamines as substrates. This paper demonstrates that N5,10-methylenetetrahydrofolate reductase (methylene reductase) is responsible for this in vitro tryptoline formation with human brain enzymatic preparations. Others have described a folate-responsive psychosis which was associated with markedly reduced methylene reductase activity. Therefore, we also have examined this enzymatic activity in autopsied brains from chronic schizophrenics and controls. There were no statistically significant differences between activities for schizophrenics and controls in the six brain regions studied. Thus, although it is possible that some subgroup of schizophrenics may be characterized by abnormal methylene reductase activity, there does not appear to be a general association between the two.

This paper reports the results of an investigation of voluntary control of lip, jaw, and tongue movements in schizophrenic patients with and without tardive dyskinesia. The aims of the study were to determine if voluntary orofacial motor control is disrupted in schizophrenia and to evaluate the relationship between voluntary motor control deficits and selected neurological and behavioral variables. Twenty-two schizophrenic patients and 13 normal control subjects were studied. Of the patients, 11 had moderate to severe TD. Analyses were made of performance on pursuit tracking tasks to evaluate differences between TD and non-TD patients and between medicated and currently unmedicated patients. The results indicated significant group differences in voluntary orofacial motor control. The finding that many non-TD patients exhibited voluntary motor dyscontrol suggests that this may represent a disorder independent of the involuntary dyskinesia. The findings indicated that the level of neuroleptic and/or antiparkinsonian medication was unrelated to the degree of voluntary motor control impairment. The results are discussed in terms of probable neurophysiological mechanisms underlying the motor control deficits in schizophrenia.

The success of lithium carbonate in the treatment of manic-depressive illness has led to its use in many other psychiatric disorders. Within this group, schizophrenia and schizo-affective disorder have come under the closest scrutiny. The literature, however, is difficult to reconcile. Conclusions are often contradictory, methodologies confusing, and well-designed studies few in number. In this paper, the authors have attempted to extract common denominators that may prove of value in delineating those symptoms which predict therapeutic response to lithium carbonate.

This paper is addressed to presenting evidence that the basal ganglia are involved in mediating schizophrenia. Data from the experimental and clinical literature suggest a basal ganglionic role in higher cognitive processes, affect, and attention. Deficits of these same factors serve to characterize the major symptoms of schizophrenia. Moreover, psychiatric patients tend to have frank motor problems characteristic of basal ganglia lesions and pathological conditions of the basal ganglia manifest psychiatric difficulties as a major symptom. Taken together, these data are in accord with the hypothesis that some dysfunction involving the basal ganglia is a major factor in schizophrenia.

Carr et al. (1978) and Rudin (1979) independently suggested tat systemic lupus erythematosus (SLE) might provide a model for schizophrenia since SLE is strongly associated with schizophreniform psychoses and exhibits only a covert CNS pathology revealed by immunofluorescent immune complex deposits in the choroid plexus. To carry the concept forward we here examine SLE employing the ideas developed in the preceding paper (Rudin, 1980) indicating that the choroid plexus is part of a second blood-brain barrier guarding the periventricular primary personality brain, the limbic system, and that the choroid plexus is also but one of a set of "transport organs" sharing common vulnerability to covert basal lamina immune complex pathology. In this context both SLE and schizophrenia are viewed as expressions of combined transport dysfunction syndromes, resulting from polygenic-induced sensitivity to exogenous peptides or viruses causing basal laminar immune complex disease, but exhibiting differing statistical expressions over the transport organ group due to difference in genes which elicit different transport organ sensitivities to different exogenous viruses or peptide antigens. Immune disease processes are briefly reviewed.

Many studies in biological psychiatry compare the abundance of individual messenger RNAs between cases and control subjects or, more recently, between genotype groups. Most utilize some form of normalization procedure, usually expressing the transcript(s) of interest relative to that of a housekeeping gene or genes (also called reference genes), to overcome various sources of experimental error. Indeed, normalization is such a standard procedure that its purpose, principles, and limitations are sometimes overlooked, and some papers lack sufficient information as to its implementation. Here, we review the rationales for normalization and argue that in well-conducted psychiatric gene expression studies using human brain tissue, it is reducing intersubject variability rather than experimental error that is the major benefit of normalization. We also review the conceptual and empirical basis for the category of housekeeping genes—i.e., genes with a ubiquitous and invariant expression. We conclude that the evidence is against any such simple categorization and that a more pragmatic, less dogmatic, approach to the selection and implementation of reference genes is required, which takes into account the particular issues that pertain to human brain tissue studies. This pragmatism extends to the issue of whether normalization should be to one or multiple reference genes. We end by making several recommendations toward a more flexible, transparent, and comprehensive approach to data presentation and analysis. We illustrate the review with examples from studies of schizophrenia and mood disorder. [Copyright &y& Elsevier]