Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

https://jamanetwork.com/journals/PSYCH/articlepdf/496531/archpsyc_51_3_004.pdf

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)

Recent advances in the phencyclidine model of schizophrenia.

Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-d-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the sym...

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.158.9.1367

The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia

Behavioural and the E E G response to various centrally active drugs has been suggested frequently as a way to distin­ guish schizophrenic populations (6,9). In following this model, intravenous thio­ pental 'has found increased use both in diagnosis and in prognosis (4,14). In a series of detailed studies, schizophrenic patients presenting an organic mental syndrome have exhibited a special sensi­ tivity to thiopental. Clinically they de­ veloped a deep narcosis and their EEGs showed enhanced delta activity (7). The aim of this study was to assess the value of a psychotomimetic com­ pound such as phencyclidinet for use in the diagnosis and prognosis of schizo­ phrenic patients. Because phencyclidine displays a dual effect in the central ner­ vous system, which is demonstrated by blocking sensory perception and pro­ ducing hallucinogenic activity (5, 11), it was selected for these investigations. Psychotomimetic activity is apparent following the administration of low dosages. In high dosages the anesthetic effect with changes in consciousness pre­ dominates. •

Effect of phencyclidine in chronic schizophrenics.

Therapeutic studies in "therapy resistant" schizophrenic patients.

Thioridazine and chlordiazepoxide, alone and combined, in the treatment of chronic schizophrenia

Previous investigations have shown that some of the major neuroleptics, such as haloperidol and fluphenazine hydrochloride, have both central inhibitory and central stimulatory effects in animals and man, depending upon the dosage level (Kamenskaya PL Aleksandrovsky (1964), Himwich & Glissori (1967), Marinato Rr Leonardi (1960), Heinemann & Ztil (1970)). In recent all-night sleep investigations we have demonstrated that potent neuroleptic compounds, such as thiothixene, haloperidol, molindone, and fluphenazine, increase awakening states during low dosage treatment, but during high dosage treatment they decrease both awakening periods and very deep sleep stages (stage 4) ( I t i l et al. (1970 a, 1971 a, b, c ) ) . Since fluphenazine hydrochloride may have different clinical effects at different dosage levels, we set up a study to evaluate the psychopathological and quantitative EEG changes in two matched groups of chronic schizophrenics. Patients were treated simultaneously with two different dosage levels of fluphenazine hydrochloride. (Prolixin@, Squibb & Son, New Brunswick, N.J).

Clinical and quantitative eeg changes at different dosage levels of fluphenazine treatment

To determine whether preference shown to female patients was due to sex alone, demographic and psychiatric data were analyzed for 137 patients referred to a rehabilitation program conducted in cooperation with rural Missouri towns. The ratio of men to women referred to the program (1.0 to 1.6) differed significantly from the hospital population considered suitable for the program (1.1 to 1.0). Men and women compared showed no significant differences in age, length of hospitalization, or diagnosis, factors which favored acceptance in general. Experiences in placing patients in the foster communities indicate men are at a disadvantage because of expectations that they be employed. This reflects stereotyped sex-role expectations and it is suggested that further evaluation is needed to determine to what extent a patient's sex influences psychiatric care.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=psych&articleId=490899&pdfFileName=archpsyc_28_5_013.pdf

Advantages of being female in psychiatric rehabilitation.

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