• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Implications of normal brain development for the pathogenesis of schizophrenia

Recent neuroradiologic and neuropathological studies indicate that at least some patients with schizophrenia have slightly enlarged cerebral ventricles and subtle anatomical abnormalities in the region of the anterior hippocampus. Using magnetic resonance imaging (MRI), we studied 15 sets of monozygotic twins who were discordant for schizophrenia (age range, 25 to 44 years; 8 male and 7 female pairs). For each pair of twins, T1-weighted contiguous coronal sections (5 mm thick) were compared blindly, and quantitative measurements of brain structures were made with a computerized image-analysis system. In 12 of the 15 discordant pairs, the twin with schizophrenia was identified by visual inspection of cerebrospinal fluid spaces. In two pairs no difference could be discerned visually, and in one the twin with schizophrenia was misidentified. Quantitative analysis of sections through the level of the pes hippocampi showed the hippocampus to be smaller on the left in 14 of the 15 affected twins, as compared with their normal twins, and smaller on the right in 13 affected twins (both P less than 0.001). In the twins with schizophrenia, as compared with their normal twins, the lateral ventricles were larger on the left in 14 (P less than 0.003) and on the right in 13 (P less than 0.001). The third ventricle also was larger in 13 of the twins with schizophrenia (P less than 0.001). None of these differences were found in seven sets of monozygotic twins without schizophrenia who were studied similarly as controls. We conclude that subtle abnormalities of cerebral anatomy (namely, small anterior hippocampi and enlarged lateral and third ventricles) are consistent neuropathologic features of schizophrenia and that their cause is at least in part not genetic. Further study is required to determine whether these changes are primary or secondary to the disease.

https://www.nejm.org/doi/pdf/10.1056/NEJM199003223221201

Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia.

Objective; This study was undertaken to assess the potential effect ofduration of untreated illness on outcome in a group offirst-episode schizophrenic patients. Method: Seventy patients with schizophrenia diagnosed according to the Research Diagnostic Criteria entered the study and were followed for up to 3 years. All patients received standardized treatment and uniform assessments both during the acute phase of their illness and throughout the follow-up period. Outcome was measured in terms of time to remission ofacute psychotic symptoms as well as degree ofsymptom remission. Results: The mean duration ofpsychotic symptoms before initial treatment was 52 weeks, preceded by a substantial prepsychotic period. According to survival analysis, duration of illness before treatment was found to be significantly associated with time to remission as well as with level ofremission. The effect ofduration ofillness on outcome remained significant when diagnosis and gender variables, themselves associated with outcome, were controlled in a regression analysis. Duration ofiliness was not correlated with age at onset, mode of onset, premorbid adjustment, or severity of illness at entry into the study. Conclusions: Duration ofpsychosis before treatment may be an important predictor of outcome in first-episode schizophrenia. Acute psychotic symptoms could reflect an active morbid process which, if not ameliorated by neuroleptic drug treatment, may result in lasting morbidity. Further implications of these findings are discussed. (AmJ Psychiatry 1992; 149:1183-1188) C onsiderable attention has been focused on clinical factors that may influence the outcome of patients

Duration of psychosis and outcome in first-episode schizophrenia.

The Dopamine Hypothesis of Schizophrenia: A Review*

The two-syndrome concept postulates two "dimensions of pathology" underlying schizophrenia--a reversible (and potentially neuroleptic-responsive) component and a sometimes progressive and relatively irreversible component associated with the deficit state and poor long-term outcome. Negative symptoms (narrowly defined) appear to be more closely associated with the latter component (the type II syndrome), as also are cognitive impairments, abnormal involuntary movements, and behavioral deterioration. This syndrome is assumed to be more closely related than the type I syndrome of positive symptoms to the structural brain changes inferred from pneumoencephalograms, computed tomography scans, and recent post-mortem studies. However, since both syndromes often occur in the same patient--sometimes at the same point in time--they presumably have the same etiology.

The Two-syndrome Concept: Origins and Current Status

Seventy-seven patients with diagnosis of schizophrenia (62) or schizoaffective disorder (15) were studied 2-20 years since onset of illness, when in a stable condition. The investigation included clinical assessment, measurement of plasma concentrations of neuroleptics and prolactin, computed tomography brain scan, neuropsychological and neurological examination. Outcome of illness was classified according to the presence of chronic psychiatric symptoms and social impairment, and response to neuroleptics according to the effect of treatment in the most recent psychotic episode. Neither outcome nor response to neuroleptics was related to duration of illness. The groups with good and poor outcome differed in premorbid adjustment, age at onset and symptoms of the initial episode, but not in drug bio-availability or prolactin response. Large cerebral ventricles and cognitive impairment, but not neurological 'soft' signs, were associated with unfavourable outcome. The three measures of organicity were not inter-related. No clinical differences were found between chronic patients with and without signs of organic dysfunction. The findings suggest that schizophrenia with good and unfavourable outcome may be separate sub-types. However, the role of organic factors in the latter group remains unclear.

Schizophrenia with good and poor outcome. I: Early clinical features, response to neuroleptics and signs of organic dysfunction.

Computer tomography brain scans were carried out on 40 patients with schizophrenia or schizo-affective disorder of 2-20 years duration. Ventricular-brain ratio (VBR) was significantly greater than that of the control group. In six patients the VBR exceeded the control mean + 2 s.d. Among the 13 whose VBR was more than 1 s.d. above the control mean, none had schizo-affective disorder, all but one had chronic illness, and patients with negative symptoms and those with premorbid schizoid traits were over-represented. VBR was unrelated to medical history, age, duration of illness, or neuroleptic treatment. It was not associated with neurological 'soft' signs or cognitive deficit. Among chronic patients, clinical features showed no association with ventricular size. The findings suggest that large ventricles may be related to a sub-type of chronic schizophrenia rather than to its particular clinical features.

Schizophrenia with good and poor outcome. II: Cerebral ventricular size and its clinical significance.

Fifteen female psychiatric patients developed inappropriate breast activity and/or amenorrhoea while receiving treatment with phenothiazines and related drugs. In the majority plasma prolactin was clearly elevated. In those whose menstruation had not been affected, circulating levels of luteinizing hormone (LH), immunoreactive oestrogens (oestradiol) and progesterone followed the normal pattern of the menstrual cycle. In amenorrhoeic subjects, basal LH values were variable, mid-cycle peaks were absent, and oestrogen and progesterone levels were similar to values reported during the follicular phase of a normal cycle.

Medication was withdrawn subsequently from four patients. Breast secretion diminished and plasma prolactin fell to within the normal range, rising again when the drugs were reinstated. In two of three amenorrhoeic patients, withdrawal of medication led to a resumption of menstruation with a normal cyclical pattern of LH, oestrogens and progesterone.

The effects of phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea.

There is ample evidence that high doses of phenothiazines and other neuroleptics depress the pituitary-gonadal axis in experimental animals (De Wied, 1967), but the effects of these drugs on sex hormones in human subjects are still controversial (Shader and Di Mascio, 1970). Literature concerning growth hormone (GH) is even more controversial, since phenothiazines have been found to inhibit GH release in rodents (Muller et al., 1967) but to increase it in the rhesus monkey (Meyer and Knobil, 1967). In human subjects phenothiazines have been reported to depress both basal levels of GH and the response to hypoglycaemia (Sherman et al., 1971), while others have found that this response is enhanced (Schimmelbusch, Mueller and Scheps, 1971). Studies of prolactin levels are more consistent, showing raised prolactin both in experimental animals and in human subjects following administration of phenothiazines (Apostolakis et al., 1972; Hwang et al., 1971; Kleinberg et al., 1971; Sulman, 1970).

B. M. Mandelbrote

Papers

Schizophrenia with good and poor outcome. I: Early clinical features, response to neuroleptics and signs of organic dysfunction.

Schizophrenia with good and poor outcome. II: Cerebral ventricular size and its clinical significance.

The effects of phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea.

The effects of phenothiazines on endocrine function: II. Effects in men and post-menopausal women.

Some endocrine effects of phenothiazines: a preliminary report.