The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

Dopamine receptors and the dopamine hypothesis of schizophrenia.

Two hundred and eighty-three chronic pain patients, consecutive admissions to the Comprehensive Pain Center of the University of Miami School of Medicine, received an extensive psychiatric evaluation based upon the American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria and flowsheets. All patients received the following type of diagnoses: DSM-III axis I; DSM-III axis II, and personality type. The distribution of assigned diagnoses for the entire patient sample was reviewed and a statistical comparison between male and female patients was performed with regards to the prevalence of each diagnosis. Anxiety syndromes and depression of various diagnostic types were the most frequently assigned axis I diagnoses with over half the patient sample receiving each of these diagnoses. Males were significantly overrepresented in the axis I diagnoses of intermittent explosive disorders, adjustment disorders with work inhibitions, and alcohol abuse and other drug dependence, while females were significantly overrepresented in disorders of current depression of various diagnostic types and somatization disorders. 58.4% of the patients fulfilled criteria for axis II personality disorder diagnoses. The most frequently personality disorders found in the patient group were dependent (17.4%), passive aggressive (14.9%), and histrionic (11.7%). Males were significantly overrepresented in paranoid and narcissistic disorders while females were overrepresented in histrionic disorder. The most frequent personality types found in the patient group were compulsive (24.5%) and dependent (10.6%). All personality types were similarly distributed between the sexes. The results of the present study were compared to a previous study of DSM-III diagnoses in chronic pain patients and are discussed in terms of the prevalence of DSM-III diagnoses in the general population. Questions are raised as to the applicability of certain DSM-III diagnoses in the chronic pain population.

Male and female chronic pain patients categorized by DSM-III psychiatric diagnostic criteria

• Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=psych&articleId=493474&pdfFileName=archpsyc_41_12_007.pdf

Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders.

Neurotransmitters and CNS disease. Schizophrenia.

The Diagnosis of Autism.- Early Symptoms in Autism.- Autism and "Theory of Mind".- Social or Cognitive or Both? Crucial Dysfunctions in Autism.- The Etiology of Autism.- Recent Neurobiological Findings in Autism.- Chromosomes, Genes and Autism.- Autism: Inmmunologiral Investigations.- The First Evaluation: Treatment Begins Here.- Educational Evaluation.- Principles for Directing Both Educational Treatment and Research.- Help for the Family.- Phannacotherapy in Autism: An Overview.- Autism: Non-Drug Biological Treatments.- Psychodynamically Oriented Psychotherapy in Autism.- Comprehensive Treatment Program for Autistic Children and Adults in Denmark.- Exchange and Development Therapies (E. D. T.) for Children with Autism: A Treatment Program from Tours.- The Nature of Behavioral Treatment and Research with Young Autistic Persons.- Treating Autistic Children at Home: A London Based Programme.- The REBECKA-Project: A Short Summary.- Habilitation for Children with Autism: A Swedish Example.- Steps Towards the Organization of Services for Autistic Children and Their Family.- State-of-the-Art Programming in Massachusetts: A Brief Description of the May Institute.- Autism: Specific Problems of Adolescence.- Pharmacotherapy of Adolescent Problems.- Educational Issues in Adolescence.- Psychotherapeutical Help in Adolescence.- Autistic Adults.- Addendum: Is the Primary Lesion in Autism Related to the Locus Coeruleus?.- Autism: Diagnosis and Treatment. The State of the Art, May 1989.- Contributors.

Diagnosis and treatment of autism.

• A double-blind study of the behavioral effects of short-term naloxone hydrochloride administration was performed in 32 schizophrenic and 26 manic patients in a World Health Organization collaborative project. There was a significant naloxoneassociated reduction in overall physician-rated symptoms in schizophrenic patients concurrently treated with neuroleptic medication (N = 19) but not in medication-free schizophrenics (N = 13). Physician ratings of auditory hallucinations showed significant naloxone-associated improvement for the total schizophrenic population, while self-ratings of auditory hallucinations showed improvement only in neuroleptic-treated schizophrenics. While further studies are needed to delineate these effects as to clinical significance, they may bear etiological implications for the psychobiology of schizophrenia, including the possibility of synergistic effects of dopamine and endorphin blockade. Naloxone produced no significant behavioral effects in manic patients. These findings are discussed with relationship to the hypotheses of endorphin involvement in schizophrenia and mania.

Hans P. Maier

Papers

Short-term Naloxone Administration in Schizophrenic and Manic Patients: A World Health Organization Collaborative Study