• 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

OBJECTIVE: The purpose of this study was to estimate and compare the effects of anti­psychotics—both the newer ones and the conventional ones—on body weight. METHOD: A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information. RESULTS: Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg....

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.11.1686

Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis

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*

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.

Fifty-six patients with RDC schizophrenia (42) or schizoaffective disorder (14), of two to 20 years' duration, were assessed for neurological 'soft' signs and cognitive impairment when in a stable condition--the 'outcome'. Neurological dysfunction (46% of 50 examined patients) was associated with a history of developmental abnormalities, but was unrelated to outcome, psychiatric symptoms, or treatment. Deficits in particular cognitive fields were related to two independent factors: overall severity of residual psychiatric disorder (outcome) and neurological dysfunction. There was no relationship between the size of the lateral brain ventricles on CT scan and either 'soft' signs or cognitive impairment. The findings do not provide evidence for an association between the presence of organic brain disorder (as indicated by the joint occurrence of neurological dysfunction and cognitive impairment) and either poor outcome or particular symptoms of schizophrenia.

Schizophrenia with good and poor outcome. III: Neurological 'soft' signs, cognitive impairment and their clinical significance.

Schizophrenia with Good and Poor Outcome SIR: The letter by Drs Nimgaonkar & Murray (Journal, March 1986, 148, 343â€”344)misrepresents some aspects of our studies (Journal, March and April 1985, 146, 229â€”246and 348â€”357).According to the opening and closing sentences of their letter, these studies illustrate the difficulty of obtaining longitudinal information from a cross-sectional study, and the design allowed us to do no more than confirm what is already known about the prognostic significance of certain clinical features. These corn ments may suggest (misleadingly) that the principal aim of our investigation was to find clinical predic tors ofoutcome in schizophrenia. In fact, it was con corned mainly with â€ ̃¿ cross-sectional' questions: whether patients with persisting schizophrenic symptoms also show signs indicating organic brain dysfunction (an abnormal CT scan, neurological soft signs and/or cognitive impairment); whether these â€ ̃¿ organic' signs are inter-related; and whether they are associated with any particular chronic psychiatric symptoms. The â€ ̃¿ longitudinal'infor mation, imperfect because obtained retrospectively, was reported to indicate whether the groups with good and poor outcome differed in the early stages of illness, especially in the quality of remission and response to neuroleptics at that time. The possibility that some of the â€ ̃¿ organic' abnor malities may have been â€œ¿ ... consequent upon poor outcome or factors associated with it .. .â€œ, was not ignored but discussed at some length in the second and third papers in the series. Though these papers presented in detail the abnormalities found and included tentative interpretations, they were some how disregarded in the letter. Further, we have not claimed that our data â€œ¿ have eliminated all likeli hood of pharmacological toleranceâ€•in patients who respond unsatisfactorily to treatment with neuro leptics. We have only said that our data on drug bioavailability and prolactin response provided no evidence for such tolerance. Finally, though our sample was not representative for the prevalence of particular types of outcome, it included the full range of outcome states, from asymptomatic remission to chronic psychosis. Drs Nimgaonkar and Murray comment disapprovingly that the non-representative character of the sample did not deter us from â€œ¿ making the sweeping general isations about possible sub-types of schizophreniaâ€•. In fact, our â€œ¿ sweeping generalisationsâ€•consisted only in supporting the distinction between sub-types with good and poor outcomeâ€”a distinction which under various names has been discussed for at least half a century.

/pdf/schizophrenia-with-good-and-poor-outcome-10emajw097.pdf

Schizophrenia with Good and Poor Outcome

Intravenous infusion of l-tryptophan (LTP) in 18 normal subjects produced a significant increase in plasma prolactin (PRL), growth hormone (GH), and self-ratings of drowsiness. There was no correlation between the PRL and GH responses, or between the hormonal responses and drowsiness. Saline infusion did not result in endocrine or psychological changes. The effect of LTP on both PRL and GH was dose-related in that LTP 7.5 g produced greater endocrine responses than 5.0 g. It was not significantly decreased by cyproheptadine, a 5-HT receptor antagonist. Schizophrenic patients receiving neuroleptics had increased PRL response to LTP, possibly because of the drug-induced disinhibition of PRL release. Their GH response to LTP was markedly decreased. The mechanism of this effect requires further investigation.

T Kolakowska

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.

Schizophrenia with good and poor outcome. III: Neurological 'soft' signs, cognitive impairment and their clinical significance.

Schizophrenia with Good and Poor Outcome

Responses of prolactin and growth hormone to L-tryptophan infusion: effects in normal subjects and schizophrenic patients receiving neuroleptics.