IQ scores of treatment-resistant schizophrenia patients before and after the onset of the illness.

In this study we examined the correlations of actual pre-morbid IQ scores (obtained from routine educational assessments) and estimated current IQ scores in 27 treatment-resistant schizophrenia patients. Pre-morbid (mean = 93) and current (mean = 83) IQ scores were significantly correlated (r = 0.807, P < 0.0001), while duration of illness (10-40 years) was unrelated to the magnitude of IQ score decline (r = -0.103, P = 0.575). These data suggest that pre-morbid IQ test scores are highly predictive of post-morbid scores.

Dyskinesias differentiate autistic disorder from catatonia.

Autistic disorder and catatonia are neuropsychiatric syndromes defined by impairments in social interaction, communication, and restricted, stereotypical motor routines. Assessments of children with these disorders are typically restricted in scope by the patients' limited ability to comprehend directions. The authors performed systematic assessments of dyskinesias on six prepubertal boys with autistic disorder and mental retardation and on one adolescent male with catatonia to determine if this type of information could be routinely obtained. The boys with autistic disorder had more stereotypies and tics, a greater degree of akathisia and hyperactivity, and more compulsions than the adolescent with catatonia. Catatonia was associated with catalepsy and dystonic postures. The authors conclude that the diagnostic accuracy and specificity of neuropsychiatric syndromes may be enhanced by the systematic assessment of the dyskinesias associated with each condition.

Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization.

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.

Progressive catatonia.

We present the case of a young man with a diagnosis of a childhood-onset pervasive developmental disorder who developed a progressive neurologic deterioration with persistent catatonia and right hemiparesis. On his initial evaluation approximately three years after the onset of mutism, he manifested right hemiparesis and catalepsy. Two years later, although catalepsy had subsided, motor function had deteriorated so that he could not use his hands to feed or dress himself. Oral-facialbuccal dyskinesia manifested by blepharospasm and grimacing were present constantly during waking hours. Quantitative electroencephalography demonstrated markedly decreased amplitude, a finding associated with catatonia. Left sural nerve biopsy indicated large axon cylinder degeneration. Left deltoid biopsy demonstrated perimysial fibrosis and type II fiber predominance. Although magnetic resonance imaging of the head without contrast was normal, positron emission tomography indicated hypometabolism of the right cerebral and the right cerebellar hemispheres. The patient continues to deteriorate despite a course of 25 electroconvulsive treatments. He continues to manifest criteria for catatonia including motoric immobility, mutism, and peculiarities of voluntary movement such as prominent grimacing. We suspect an inherited neurodegenerative disorder. Since catatonia is a treatable condition frequently associated with medical and neurological diseases, examination for the features of catatonia must be included in the assessment of patients with progressive brain degeneration. This report is an attempt to clarify the traits of a serious variant of progressive brain degeneration.

An integrated view of pathophysiological models 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.

The natural history and pathophysiology of treatment resistant schizophrenia.

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.

Clinical assessment of adventitious movements.

Many procedures with variable validity and reliability have been developed in research settings to evaluate adventitious movements and related phenomena in specific populations, e.g., people with schizophrenia treated with dopamine antagonists, but these only provide global assessments or rate specific movements. A battery for rating individuals with possible movements disorders in a comprehensive way in clinical settings is needed so a protocol to assess briefly and thoroughly potential movement disorders was videotaped for five prepubertal boys with autistic disorder and severe mental retardation in a clinical trial. Utilizing a Movement Assessment Battery, four raters independently scored videotapes of 10-16 movements assessments of each of the five subjects. Experienced raters attained agreement of 59% to 100% on ratings of tardive dyskinesia and 48% to 100% on tics. Hindrances to reliability included poor quality of some tapes, high activity of subjects, and fatigue of raters.

Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity.

Existing pathophysiological models of schizophrenia are limited in their ability to account for all the clinical dimensions of the disorder. The purpose of this article is to describe a comprehensive hypothesis of the pathophysiology of schizophrenia and specifically how a deficit in neural regulation of developmental origin can lead to a pathologic form of neuroplasticity, i.e., neurochemical sensitization, which causes the onset and psychotic symptoms of the illness. We propose that the symptoms of schizophrenia may be caused by deficits in neural regulation resulting in a pathologic condition of neurochemical sensitization analogous to the preclinical model of pharmacologically-induced behavioral sensitization. This condition, if sustained, can lead to potential neurotoxic effects which produce structural neuronal alterations and persistent morbidity. Several lines of indirect and direct clinical evidence are consistent with this hypothesis. These include the ability of stimulant and psychotomimetic drugs to induce psychosis in normal subjects, the development of apparent sensitization to psychosis-inducing effects of stimulants in chronic stimulant abusers and the increased susceptibility of patients with schizophrenia to the psychotogenic effects of Dopamine (DA) agonists. This hypothesis integrates and extends the work of other investigators and is consistent with specific aspects of the longitudinal course of schizophrenia. The association of longer duration and more episodes of psychosis, with poor treatment response and outcome, are also consistent with this model. Form this hypothesis, specific predictions about the illness course, treatment interventions, and pathophysiologic features of schizophrenia can be derived and tested through clinical investigation.

The evaluation and treatment of first-episode psychosis.

A first episode of psychosis is a traumatic experience for patients and families. At the time of initial evaluation, the differential diagnosis should include a broad range of neurological, general medical, and psychiatric conditions. Methodological advances in operationally defining illness onset, "offset," and remission have allowed more careful studies of treatment response in first-episode patients. These studies strongly support the efficacy of antipsychotic medication as both acute and maintenance treatment for patients with a first episode of psychosis. The optimal duration of maintenance treatment, however, has not been determined, and patients at low risk for relapse following medication withdrawal cannot be identified with specificity. First-episode psychotic patients typically experience 12 to 24 months of psychosis before receiving treatment, and a long duration of untreated psychosis may be associated with a poorer treatment response. Early intervention may improve outcome in first-episode psychosis, and the use of novel antipsychotics with improved efficacy and fewer side effects may improve medication compliance and reduce morbidity associated with repeated relapses.

Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation.

In an open, nonblind clinical trial, clomipramine reduced adventitious movements and compulsions in five previously medicated prepubertal boys with autistic disorder and severe mental retardation. Poorly adapted rating scales, interrater variability, subject heterogeneity, different treatment histories, and environmental stresses confounded the assessment of treatment effects.