Serum concentrations of the third and fourth components of the complement system and total complement haemolytic activity were measured in 167 psychiatric patients. Total complement haemolytic activity was decreased in chronic schizophrenic patients as compared to healthy controls and bipolar patients. The relatively diminished total haemolytic activity was not attributable to drug treatment. It is not clear if the reduced total haemolytic activity is an epiphenomenon or related to the involvement of an autoimmune process in the pathophysiology of schizophrenia.

A critical examination is made of the role that statistical methods have played in the understanding of depression. The development of instruments for measuring depression is illustrated by reference to the Beck Depression Inventory and the Hamilton Rating Scale. The controversy over the existence of one or two types of depression is examined from the perspective of the statistical tools used. Some of the problems in studies of the heritability of depression are outlined. The development of clinical trials of depression is examined, with particular reference to ECT and maintenance therapy, and the role of meta-analysis is discussed.

We have previously reported focal abnormalities of regional cerebral blood flow (rCBF) in a group of 33 patients with major depression. This report, on an extended sample of 40 patients who demonstrated identical regional deficits to those previously described, examines the relationships between depressive symptoms and patterns of rCBF. Patients' symptom ratings were subjected to factor analysis, producing a three-factor solution. The scores for these three factors, which corresponded to recognizable dimensions of depressive illness, were then correlated with rCBF. The first factor had high loadings for anxiety and correlated positively with rCBF in the posterior cingulate cortex and inferior parietal lobule bilaterally. The second factor had high loadings for psychomotor retardation and depressed mood and correlated negatively with rCBF in the left dorsolateral prefrontal cortex and left angular gyrus. The third factor had a high loading for cognitive performance and correlated positively with rCBF in the left medial prefrontal cortex. These data indicate that symptomatic specificity may be ascribed to regional functional deficits in major depressive illness.

The hypothesis tested was that, in schizophrenia, corpus callosum size would be reduced, particularly in the region responsible for communication between both temporal lobes. This is supported by knowledge of: (a) anatomical homotopicity and functional specialization of fibres within the corpus callosum; (b) evidence linking structural and functional deficits of the corpus callosum and left temporal lobe with schizophrenia; and (c) that temporal lobe neuronal fibres pass through the middle region of the corpus callosum. Brain area and corpus callosum areas, widths and length were measured on mid-sagittal MRI scans using a computer outlining method. Scans from 30 schizophrenics and 44 normal subjects were compared. Mid-sagittal brain area, corpus callosum area, length and anterior widths were reduced in the schizophrenic group compared with controls. A significant area difference between schizophrenics and controls was seen in the mid-corpus callosum which communicates between the temporal lobes, including the superior temporal gyri. In schizophrenics, corpus callosum area reduction was not accounted for by brain area shrinkage alone. Differences between the two groups were accounted for by comparisons between males only. These findings support the hypothesis and the possibility that localized abnormalities of bilaterally connected brain regions might have secondary effects on their homotopically distributed fibres within the corpus callosum.

Many structural brain abnormalities have been described in schizophrenia, consistent with a neurodevelopmental model for this disease. We report here a study of the cavum septum pellucidum (CSP) in schizophrenia compared to control groups, as well as the clinical correlates of this congenital anomaly in schizophrenia. We conducted a magnetic resonance imaging (MRI) study to compare rates of CSP in schizophrenia (N = 67) v. psychiatric controls (bipolar and schizoaffective, N = 60) and healthy controls (N = 37). Of the controls 18·9 %, and of all psychotic subjects 18·1 % had a CSP of any size and there was no difference in the frequency of large CSP among the groups. Males had higher rates of CSP than females (25% v. 9·7%, P = 0·01) in all groups. Schizophrenics had higher CSP rates than affective patients (25%, v. 10%, P = 0·02). No clinical difference was found between schizophrenics with or without CSP.

The MRI scans of 48 schizophrenic patients, fulfilling RDC criteria, were compared to those of 34 healthy controls matched for age, ethnicity and parental social class. The volume of the frontal and anterior parietal lobes was significantly reduced in the schizophrenic group as a result of a selective decrease in cortical volume, with a corresponding increase in the volume of sulcal fluid. Reduction in the volume of the temporal grey matter was more marked on the right, but was not in excess of the loss of volume observed in other areas of the cortex. MRI abnormalities correlated poorly with clinical parameters, although both unemployment and poor pre-morbid adjustment predicted reduced cerebral volume and increased sulcal volume. These results question whether the medial temporal lobes are the only site of structural pathology in schizophrenia.

Clinical epidemiology, a term that has been variously defined, is used here to refer to a discipline which, commencing with examination and diagnosis of the individual patient who presents in medical practice, proceeds to study the occurrence of similar, possibly connected cases in the local community, and in so doing may provide hypotheses for population-based studies of disease and its risk factors. While the relevance of this discipline to the modern practice of clinical psychiatry remains largely unexplored, its importance in the search for causes of mental disorder is attested by many instances, both historical and more recent, in which the spread or clustering of psychiatric syndromes in populations could be related to nutritional deficiency, infectious disease, the presence of environmental neurotoxins, the social communication of psychopathology or the transmission of abnormal, harmful behaviour patterns within family groups. Observations made in clinical practice have repeatedly served as the starting point for epidemiological investigation of mental disorders, while conversely epidemiological findings have influenced clinical thinking about their classification, diagnosis, prognosis and morbid risk. A review of the relevant literature underlines the need for a keener awareness of environmental risk factors and a fundamentally epidemiological frame of reference in trying to grapple with the aetiological problems of mental disorder.

Clonidine (1·3 μg/kg) was administered to 62 control and 55 depressed patients free of psychoactive drugs for at least 7 days and fasted overnight. Growth hormone (GH), pulse, blood pressure and sedation were measured every 15 min for 1 h before and 2 h after clonidine infusion.

GH response did not differ significantly between control and depressed subjects overall or when divided by sex. The systolic hypotensive and sedative responses were blunted in depressed subjects compared with controls; these effects appeared to be secondary to residual antidepressant drugs since the differences were only significant for those depressed subjects with short drug-free intervals.

No differences between depressed subjects and controls were seen in diastolic hypotensive or bradycardic responses and no differences in GH, cardiovascular or sedative responses were found between endogenous and non-endogenous depressed subjects.

Elevation of serum creatine kinase (CK) concentrations occurs almost invariably in neuroleptic malignant syndrome (NMS). However, the role of CK levels in the diagnosis of the syndrome remains controversial. This study measured CK levels in patients who became pyrexial while on psychotropic medication and thereby mimicked some of the features of NMS. In all of these cases a diagnosis of infectious illness was made and patients responded to appropriate antibiotic therapy without alteration in psychotropic medication. Two other groups were studied for comparison – patients on psychotropics who were apyrexial and patients who became pyrexial but were not on psychotropics. Significant, unexpected elevations of CK were documented in 70% of those patients who became pyrexial while on psychotropics – in three cases elevation of concentrations to more than 1000 IU/1 (ten times reference value) were found. Thirty per cent of patients who became pyrexial but were not on psychotropics also developed elevation of CK but this was of a much smaller magnitude (lt; 200 IU/1 in five out of six cases). The results of the study suggest that elevation of CK is a non-specific finding, particularly in patients who become pyrexial on psychotropics. Use of CK as a diagnostic criterion may lead to overdiagnosis of NMS.

Using strict diagnostic criteria, 91 patients with multiple sclerosis (MS) were identified in a defined population of 112000. Of these patients, 29 were found to have been referred to a psychiatrist at least once. Their psychiatric records were searched for cases of MS presenting as a pure psychiatric disorder. Only 18 of the 30 psychiatric referrals before the diagnosis of MS involved purely mental symptoms, and there was no reason to suppose most of them to be related to MS. This study highlighted the problem of how to define a true psychiatric presentation of MS. The uncovering of two likely candidates among a population-based sample of 91 supported the existence of such a phenomenon, but it was concluded that the only way to ascertain how often purely mental symptoms might be the first manifestation of MS would be to conduct a large population-based study with controls.

Apomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 μg/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 μg/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.

Immediate memory for visuospatial information was assessed in patients affected by Alzheimer-type dementia but with unimpaired visuo-perceptual functions. Patients were given two tasks: one was a traditional visuospatial memory task (Corsi's block tapping test), the second explored specifically immediate memory for visuospatial patterns. The experiment was conducted in two parallel groups of patients in Italy and the United States, each with its own appropriate sample of normal control subjects. Results showed a specific deficit of visual working memory in demented patients, even in a task in which control subjects achieved error-free performance. These data are interpreted in the light of the Working Memory Model, and suggest that in dementia the functions of the Visuospatial Scratchpad, unlike the functions of the verbal subsystems, may be impaired.

Learning and memory were assessed in 24 monozygotic (MZ) pairs of individuals discordant for schizophrenia or delusional disorder and seven normal pairs of MZ twins. On declarative memory tasks, the affected group displayed a pattern that might best be characterized as dysmnesic in that they performed significantly worse than the discordant unaffected group on story recall, paired associated learning, and visual recall of designs, but they learned over time, had relatively preserved recognition memory, and did not show profoundly accelerated rates of forgetting. Effortful, volitional retrieval from the lexicon, measured by verbal fluency, was also compromised in the affected group. On the other hand, procedural learning of the motor skill in a pursuit rotor task was relatively intact in the affected group. Comparisons of the normal group and unaffected group indicated that the latter group had very mild impairments in some aspects of episodic memory, namely, immediate and delayed recall of stories and delayed recall of designs. It is highly unlikely that the impairments observed in the affected group can be attributed to differences in genome, family environment, socioeconomic circumstance, or educational opportunity, as all of these were controlled by the twin paradigm. Rather, the impairments appear to be related to the intercession of disease. The neuropsychological profile is consistent with frontal lobe and medial temporal lobe dysfunction, as noted in this sample as well as other samples of schizophrenic singletons. Significant correlations between many measures of memory and global level of social and vocational functioning within the discordant group were also found. Thus difficulties in rapidly acquiring new information and propitiously retrieving old information may burden patients with schizophrenia in many of the transactions of everyday life.

The goal of this study was to examine the familial resemblance of schizotypic traits, and to explore whether different schizotypic traits are familially related to one another. Several of the Chapmans' psychosis proneness scales were administered to a group of college students and their families. Evidence of at least some familial resemblance was found for both physical anhedonia and perceptual aberration, though it was stronger for anhedonia. Anhedonia and perceptual aberration appeared to be familially influenced independently of one another. Finally, the results indicated that offspring resembled their mothers more than they resembled their fathers on both anhedonia and perceptual aberration.

One hundred and six HIV-positive drug users were tested with a two-tone auditory evoked potential (AEP) task and a small battery of neuropsychological tests, to examine the relationship between the latency of the P300 component (P3) of the AEP, intellectual function, mood and drug use. Principal components analysis revealed a significant correlation between P3 latency and the first principal component (r = −0·43, P < 0·001). Varimax rotation generated three orthogonal components which we interpreted as intellectual performance, memory, and mood. Intellectual performance and self-reported mood were individually correlated with P3 latency, but memory was not (r = −0·36, P < 0·001; r = 0·23, P < 0·05; and r = −0·18, NS, respectively).

Subjects with symptomatic HIV disease had a higher correlation between P3 latency and intellectual performance than subjects with asymptomatic HIV disease and, among patients with symptomatic HIV disease, poorer memory was associated with a lower CD4 count. Opiate or benzodiazepine consumption did not correlate with poor intellectual performance, memory, or selfrated mood in our sample. These results indicate that there is a relationship between AEP latency and neuropsychological measures of intellectual function, and that it is influenced by subjective mood. Surprisingly, declared current drug use has no discriminable effect on these relationships.

Family history of Alzheimer's disease (AD) was investigated using a telephone re-interview of 99 cases and 116 controls selected from a case–control study of 170 matched pairs. It was found that the family history method used in the initial interview was satisfactory in identifying first-degree relatives and assessing their ages of birth and death, but the number of first-degree relatives suffering from AD was probably under-estimated. Family history of AD was confirmed as a risk factor for AD. Higher estimates of cumulative incidence were obtained among case relatives than among control relatives. No evidence was found to support the hypothesis that a familial form of AD is more common in those with earlier onset AD (before age 75) in those who display early, prominent features of aphasia or apraxia, or that an AD gene may be sex-linked. The curves for cumulative incidence showed no tendency to reach an asymptote, as is implied by the theory that some forms of AD are due to the action of an autosomal dominant gene. Estimates of lifetime risk by age 90 were within the range found by other investigators. Much larger samples of the very old are needed to obtain estimates of total lifetime risk with smaller standard errors.

Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have worked out a systematic search strategy. Since epidemiological distribution patterns consistently deviating from expected values provide valuable indications of causal relationships, we chose the higher age of females at first admission for schizophrenia, first reported by Kraepelin and since then confirmed in over 50 studies, as the basis for our study. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for selection and diagnostic artefacts and by testing alternative explanations at the individual stage of the study. To check whether the difference in age at first admission was determined by a difference in age at onset, a representative sample of 267 first-admitted patients with non-affective functional psychosis was examined by using an interview for the retrospective assessment of the onset of schizophrenia (IRAOS) designed for this purpose. Any of the definitions of first-ever onset applied – first sign of mental disorder, first psychotic symptom, first acute episode – led to a significant age difference of 3·2 to 4·1 years between the sexes. The distribution of onsets across the life cycle showed a later increase and a second, lower peak between the ages of 45 and 54 years among females compared with males. The lifetime risk for schizophrenia was equal for males and females. After testing the plausibility of psychosocial versus biological explanations we hypothesized that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal experiments and post mortem analyses showed that chronic oestrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism to human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appears to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.

This study compared clinically depressed subjects with normal controls on a range of working memory tasks. The findings suggested the articulatory loop and visuospatial sketch pad components of working memory to be unimpaired in depression. On a range of clinical tasks likely to involve central executive function, depressed subjects showed impairment only on some tasks.

The performance on four drawing tasks was studied in a sample of patients with verified Alzheimer's disease in order to examine the relationship of ‘constructional apraxia’ to neuropathological changes in the parietal lobe and in other brain areas. Twenty-three patients were able to attempt to copy pentagons, a spiral and a three-dimensional drawing of a house, 22 patients were able to draw a clock-face spontaneously. The results were rank-ordered by two independent raters. The values obtained in the different drawing tasks were correlated significantly with each other, with global estimates of cognitive performance (CAMCOG, Mini-Mental State), with a shorter duration of illness, higher brain weight (in the subsample of female patients), higher counts of large neurons in the parahippocampal gyrus and hippocampus, but not in the parietal lobe. This suggests that there is no specific relationship between ‘constructional apraxia’ and neuropathological changes in the parietal lobes of patients with advanced Alzheimer's disease, but that there is a correlation between widespread brain changes and several neuropsychological deficits, one of them being drawing disability.

Parental representation was assessed with the Parental Bonding Instrument (PBI) in 12 monozygotic (MZ) and 19 dizygotic (DZ) same-sexed twin pairs discordant for DSM-III-R schizophrenia. The schizophrenic twins reported less care and more overprotection from both parents than the non-schizophrenic co-twins. Multiple regression analysis disclosed that the results were independent of sex and age. Furthermore, the analysis demonstrated that whether the twins were monozygotic or dizygotic had no impact on the results. A stepwise discriminant analysis showed that difference in perceived paternal protection was the most important variable distinguishing between schizophrenic probands and their non-schizophrenic co-twins.