David L. Copolov

Positive and negative symptoms in the psychoses: Multidimensional scaling of SAPS and SANS items

Recently, the validity of the simple dichotomy between positive and negative symptoms in psychosis has been questioned. A newly admitted group of 114 DSM-III patients with psychotic disorder were assessed using Andreasons positive and negative symptoms scales. Multidimensional scaling, augmented by cluster analysis, was applied to the full item set of these scales and showed clearly that there are three major, independent groups of symptoms: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. Within the Hallucinations/Delusions and Negative Symptoms groups there was some additional structure which does not conform to the SAPS and SANS sub-scales. In particular there was considerable heterogeneity within the Hallucinations/Delusions group, and delusions of persecution may represent a fourth independent dimension of psychopathology which is under-represented in these scales.

Positive and negative symptoms in the psychoses: Re-analysis of published SAPS and SANS global ratings

The validity of the simple dichotomy between positive and negative symptoms was examined by reanalysing the results of published studies using global ratings from Andreasens SAPS and SANS. Global ratings from our own sample of 114 diagnostically heterogenous psychotic patients were also analysed. In none of the studies was a simple positive-negative dichotomy an adequate representation of symptom structure. The most commonly occurring structure consisted of three independent groups: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. These findings applied to both manic and schizophrenic groups of patients. An important implication of these results for future studies is that combining positive symptoms into a single scale is inappropriate because possibly differential relationships between Hallucinations/Delusions and Thought Disorder and a variety of external measures may be obscured by such a means of data reduction.

Muscarinic 1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1, 2, 3, 4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean ± SEM: 103 ± 16 vs106 ± 17 fmol [35S]oligonucleotide probe g−1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor.

Current concepts in functional psychosis: The case for a loosening of associations

The recent explosion in knowledge in the neurosciences has heightened both the expectation of significant progress in understanding the underlying mechanisms involved in the psychoses as well as frustration over the failure of such progress to occur. As biological sophistication increases, it contrasts with the obsolescence of our nosological tools, which, through their influence upon research strategy, constitute a potential obstacle to progress. Currently dominant nosological paradigms are heavily based upon assumptions concerning the links between pathophysiology and symptoms, and between symptoms and the more distal consequences of disease. This review seeks to illustrate that the linkages between disease and its consequences are in fact much looser and more plastic than acknowledged by existing paradigms, which are constrained by tradition. Since faulty assumptions concerning these linkages are so fundamental to the current nosology, it is argued that major reform is necessary. While this can be justified on research grounds alone, there are also compelling clinical reasons why reform of this kind is important and overdue.

From Pharmacotherapy to Pathophysiology: Emerging Mechanisms of Apolipoprotein D in Psychiatric Disorders

Apolipoprotein D (apoD) is an atypical plasma apolipoprotein and, based on its primary structure, it is a member of the lipocalin protein superfamily. Lipocalins have been extensively used as disease markers and, accordingly, apoD has become increasingly recognized as an important factor in the pathology of human neurodegenerative and neuropsychiatric disorders. ApoD expression is increased in the plasma and brains of subjects with schizophrenia and bipolar disorder, suggesting that it acts as a marker for disease pathology. ApoD also exhibits complex regulation by antipsychotic drug treatment and may represent a distinguishing mechanism of typical versus atypical drugs. The precise role of apoD in the CNS and disease remains to be elucidated, but recent findings have suggested that it plays an important role in the regulation of arachidonic acid signaling and metabolism providing further support for phospholipid membrane pathology in schizophrenia.

Basal and haloperidol-stimulated prolactin in neuroleptic-free men with schizophrenia defined by 11 diagnostic systems

Forty-four male, neuroleptic-free, acutely psychotic patients with at least one diagnosis of schizophrenia among 11 diagnostic systems, and 28 healthy controls, underwent measurement of prolactin (PRL) concentrations before and after intravenous administration of haloperidol (0.5 mg). Basal PRL concentrations were lower in the patients with Research Diagnostic Criteria (RDC) DSM-III, Cloninger, and Taylor and Abrams schizophrenias than in controls. Compared with the controls, the PRL response to haloperidol was lower in the patients with schizophrenia defined by all diagnostic systems except those of Schneider and M. Bleuler. Neither basal nor stimulated PRL concentrations were correlated with positive symptoms, but basal PRL was correlated with the Brief Psychiatric Rating Scale (BPRS) depression-related subscore. This study lends further support for the presence of dopaminergic dysfunction in schizophrenia, and demonstrates the advantages and problems in the use of multidiagnostic psychopathological evaluation to categorize a disorder where there is major disagreement among diagnostic systems.

Relationship of psychotic symptoms to haloperidol-stimulated prolactin release.

Prolactin (PRL) response to a single dose of intravenous haloperidol (0.5 mg) was measured as a marker of tuberoinfundibular dopamine (TIDA) activity in 24 neuroleptic‐free, male, psychotic patients. The PRL responses were then correlated with psychotic symptoms measured with Andreasens Scales for the Assessment of Positive and Negative Symptoms (SAPS, SANS). Correlation analyses revealed a significant inverse relationship between PRL response and the severity of delusional symptoms. There was no significant correlation between the symptoms of hallucinations, formal thought disorder, or global negative symptoms and PRL response to haloperidol, nor were there any significant correlations between basal PRL and symptom severity. These results suggest that among the positive and negative symptoms associated with psychoses, only delusions may be associated with TIDA overactivity.

Multidiagnostic evaluation of prolactin response to haloperidol challenge in schizophrenia: Maximal blunting in Kraepelinian patients

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.

Prolactin response to low-dose haloperidol challenge in schizophrenic, non-schizophrenic psychotic, and control subjects

Haloperidol was administered IV to 46 male psychotic inpatients and 28 male control subjects. A two-way analysis of covariance, with age as the covariate, revealed that DSM-III schizophrenics (n = 27) had a lower prolactin response to haloperidol than did the controls (n = 28). There were no significant differences between the prolactin responses in schizophrenics, patients with affective disorders (n = 7), and those with other psychoses (n = 12), which included patients with paranoia, schizophreniform, schizoaffective disorder, and atypical psychoses. These findings support the proposition that tuberoinfundibular dopaminergic dysfunction may occur in certain patients with DSM-III schizophrenia.

Comparison of participants and nonparticipants in a neuroendocrine investigation of psychosis

Of all neuroleptic‐naive, acutely psychotic subjects admitted to hospital over a 2‐year period (n= 62), 27 participated in a neuroendocrine study and 35 did not participate (51% refused consent, 19% were incapable of consent and 31% started neuroleptics immediately). However, all nonparticipants agreed to psychopathological evaluation, thus allowing comparison between participants and nonparticipants. The 2 groups were similar in most respects, except that more nonparticipants were hostile. Among subjects with schizophrenia, 47% of nonparticipants had the paranoid subtype vs 8% of participants. There was also a trend towards longer illness duration in nonparticipants. These results underline the need for neurobiological studies of psychosis to consider sample bias as a confounding variable.