Oxygen radicals and neuropsychiatric illness. Some speculations.

Free radicals are reactive chemical species with an unpaired electron that are produced through a variety of physiologic and pathologic processes. Free radicals have been implicated in a variety of neuropsychiatric conditions, many of which are marked by the gradual development of psychopathologic symptoms and movement disorder. There is evidence that radical-induced damage may be important in Parkinson's disease, tardive dyskinesia, metal intoxication syndromes, and Down's syndrome, and possibly also in schizophrenia, Huntington's disease, and Alzheimer's disease. Although some of this evidence is highly speculative, it may offer an avenue for further understanding and treatment of these conditions.

Hippocampal pathologic findings in schizophrenia. A morphometric study.

We studied hippocampal sections from 13 schizophrenic patients, 9 nonschizophrenic patients, and 16 normal controls from the Yakovlev brain collection. The three groups were similar in age, gender distribution, and brain weight. Most patients had never received neuroleptics, and the two patient groups had had similar types of leukotomies. We used a semiautomated image analysis system to compute volume and pyramidal-cell density in each of the four sectors of the cornu ammonis, Ca1 through CA4, in the right and left hippocampi. Sections from schizophrenic patients had almost consistently the lowest volume and pyramidal-cell density in all sectors. The differences were greatest in left CA4, with schizophrenic patients having significantly lower pyramidal-cell density than normal controls and significantly lower volume than leukotomy controls. Our findings confirm the results of several recent studies showing hippocampal pathologic features in schizophrenia. Our study suggests, however, that the hippocampal neuropathologic findings in schizophrenia may be more subtle and more localized than those reported previously.

A disturbance in the control of muscle force in neuroleptic-naive schizophrenic patients.

The voluntary motor disturbances found among many schizophrenic patients consist of motor incoordination, disturbed pursuit tracking, difficulty following movement sequences, desynchronized tapping, and a myriad of neurologic soft signs. The problem with many of these observations is that it is extremely difficult to distinguish movement disorders related to neuroleptic treatment from those that may have occurred spontaneously. The aim of the present study was to examine potential disturbances in the voluntary control of steady-state force in neuroleptic-naive schizophrenic patients and normal comparison subjects. Twenty-one patients and 21 age- and gender-matched comparison subjects were studied. Spectral analyses of hand force instability revealed a significant difference between patients and comparison subjects. In 52 of the patients, the disturbance in the control of force exceeded the 95th percentile of the comparison mean. Degree of force instability was correlated with positive but not negative symptoms of schizophrenia. These findings suggest that schizophrenic patients may exhibit a disturbance in the control of muscle force that cannot be attributed to the neuroleptic effects of antipsychotic medication. The pattern of disruption, characterized by abnormal spectral energy within the 1.5 to 3.0 Hz range, suggests a motor disturbance that resembles tardive dyskinesia. Implicit within these findings of neuroleptic naive patients is the possibility that disturbances in the control of isometric force may represent spontaneous dyskinesia.

Cerebellar pathology in schizophrenia? A neuronometric study.

We have reviewed clinical, neuroradiological, and neuropathological studies of cerebellar pathology in schizophrenia. The literature suggests that a proportion of schizophrenic patients may have possible cerebellar pathology, but the specificity and exact nature of any such pathology are open to question. We conducted a neuronometric study of principal efferent neurons in cerebella from the brains of 23 leucotomized schizophrenic patients, 23 leucotomized controls, and 37 normal controls in the Yakovlev Collection. There were no significant differences among the three groups in Purkinje cell density in anterior vermis, posterior vermis, or hemispheres; size of the Purkinje cell or its nucleus in anterior vermis; or multipolar cell density in dentate nucleus. Various possible explanations for our findings are considered.

Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms?

BACKGROUND: Some studies of premenopausal women suggest that the severity of psychopathology associated with schizophrenia may be related to levels of estrogen. METHODS: We examined psychopathology in community-dwelling postmenopausal women with schizophrenia who had received (n = 24) versus had never received (n = 28) hormone replacement therapy. RESULTS: Users of hormone replacement therapy and nonusers did not differ significantly with respect to age, ethnicity, education, age of onset, duration of schizophrenia, global cognitive functioning, or neuroleptic-induced movement disorders. The hormone replacement therapy users received lower average daily doses of antipsychotic medication; they had similar levels of positive symptoms but significantly less severe negative symptoms compared with hormone replacement therapy nonusers, independent of differences in antipsychotic dosage. CONCLUSIONS: Our results suggest that the use of hormone replacement therapy in conjunction with antipsychotic medication in postmenopausal women with schizophrenia may help reduce negative, but not positive, symptoms.

Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study.

Genes that predispose to psychosis may act by making individuals more vulnerable to the disruptive effects of various prenatal insults. Fetal organogenesis is mostly completed in the first prenatal trimester. The second trimester is a critical period of massive neuronal migration from the periventricular germinal matrix to the cortex. A peripheral appendage developing simultaneously with this neural migration to the cortex is the distal upper limb. The ectodermal cells of the fetal upper limb migrate to form the hand skin during the fourth and fifth months of gestation (first two-thirds of the second prenatal trimester). Discrepancies in hand morphology between two identical (monozygotic [MZ]) co-twins may be temporal markers, that is, the "fossilized" evidence of various ischemic and other nongenetic insults that may have affected one fetus more than his MZ co-twin during that early part of the second trimester. In twins, prenatal insults (e.g., ischemia) frequently do not affect both co-twins to the same extent, so we examined seven putative markers of prenatal injury to the hand in 24 MZ twin pairs discordant for schizophrenia or delusional disorder. Compared with well co-twins, the affected co-twins had significantly higher total scores of fourth- and fifth-month dysmorphological hand anomalies.

Clinical and instrumental assessment of neuroleptic-induced parkinsonism in patients with tardive dyskinesia.

We evaluated 21 right-handed psychiatric patients with tardive dyskinesia (TD) for the presence and laterality of neuroleptic-induced tremor and rigidity. The goals of the study were to assess the frequency and coexistence of TD and neuroleptic-induced parkinsonism (NIP) using instrumental and clinical measurements and to evaluate the hypothesis that when TD and NIP coexisted in the same patient, they were more likely to appear in opposite limbs. Results indicated that a high percentage of TD patients had coexisting rigidity and tremor on the basis of both clinical ratings and instrumental procedures; however, only instrumental procedures were useful in identifying tremor and rigidity asymmetries. We found that TD and tremor or rigidity did not lateralize to opposite limbs, thus weakening the hypothesis that TD and NIP stemmed from reciprocal pathophysiological mechanisms.

Diazepam for catatonia.

Intravenous diazepam rapidly relieved catatonic immobility in two schizophrenic patients, and oral diazepam maintained this therapeutic effect. Diazepam may be an immediately available and effective treatment for some patients with life-threatening catatonic disorders.

A monozygotic mirror-image twin pair with discordant psychiatric illnesses: a neuropsychiatric and neurodevelopmental evaluation.

One piece of genetic evidence for the biological distinctness of schizophrenia and bipolar illness is the rarity of monozygotic twin pairs in which one twin suffers from schizophrenia and the other from bipolar disorder. The authors describe a pair of monozygotic mirror-image twins with discordant diagnoses, schizophrenia in one twin and bipolar or schizoaffective disorder in the other.

Parkinsonism in neuroleptic-naive schizophrenic patients.

OBJECTIVE: Previous studies in schizophrenia have identified abnormalities involving the basal ganglia, but the contribution of neuroleptics to the motor system abnormalities in schizophrenia is usually a confounding factor. This study addressed the issue of whether parkinsonism, a reflection of dopaminergic hypofunction, occurs in schizophrenia per se. METHOD: Clinical ratings and quantitative instrumental measures of parkinsonian rigidity, tremor, and bradykinesia were obtained in 24 neuroleptic-naive schizophrenic patients and 24 age- and gender-matched comparison subjects. RESULTS: According to the clinical ratings, 21% of the schizophrenic patients had rigidity and 12% had bradykinesia, in contrast to none of the normal comparison subjects. With the use of instrumental measures, rigidity and tremor were observed in 29% and 37%, respectively, of the schizophrenic patients, compared to 4% and none in the normal comparison group. The schizophrenic patients also exhibited greater right-side than left-side parkinsonism. CONCLUSIONS: The findings suggest that extrapyramidal motor signs may be part of schizophrenia proper and that some patients with schizophrenia have left striatal hypodopaminergia unrelated to neuroleptic treatment.

High prevalence of visual hallucinations in research subjects with chronic schizophrenia.

The authors examined the prevalence of visual hallucinations in severely ill hospitalized research subjects with carefully diagnosed chronic schizophrenia and found it to be high. A chart review of 100 discharged subjects revealed documentation of visual hallucinations in 32%, and a prospective examination of 43 additional subjects revealed a history of visual hallucinations in 56% (N = 24). Also, the fact that in 43% of the patients with visual hallucinations the history of visual hallucinations was first documented during the research ward work-up suggests that clinicians frequently do not inquire about visual hallucinations in patients with chronic schizophrenia.

Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients.

OBJECTIVE: The cortical-striatal-thalamic circuit modulates cognitive processing and thus may be involved in the cognitive dysfunction in schizophrenia. The imaging of metabolic rate in the structures making up this circuit could reveal the correlates of schizophrenia and its main symptoms. METHOD: Seventy male schizophrenic patients underwent [18F]-fluorodeoxyglucose positron emission tomography after a period of at least 4 weeks during which they had not received neuroleptic medication and were compared to 30 age-matched male normal comparison subjects. RESULTS: Analyses revealed decreased metabolism in medial frontal cortex, cingulate gyrus, medial temporal lobe, corpus callosum, and ventral caudate and increased metabolism in the left lateral temporal and occipital cortices in the schizophrenic cohort. Consistent with previous studies, the schizophrenic group had lower hypofrontality scores (ratios of lateral frontal to occipital metabolism) than did comparison subjects. The lateral frontal cortical metabolism of schizophrenic patients did not differ from that of comparison subjects, while occipital cortical metabolism was high, suggesting that lateral hypofrontality is due to abnormalities in occipital rather than lateral frontal activity. Hypofrontality was more prominent in medial than lateral frontal cortex. Brief Psychiatric Rating Scale (BPRS) scores, obtained for each schizophrenic patient on the scan day, were correlated with regional brain glucose metabolic rate. Medial frontal cortical and thalamic activity correlated negatively with total BPRS score and with positive and negative symptom scores. Lateral frontal cortical metabolism and hypofrontality scores did not significantly correlate with negative symptoms. Analyses of variance demonstrated a reduced right greater than left asymmetry in the schizophrenic patients for the lateral cortex as a whole, with simple interactions showing this effect specifically in temporal and frontal cortical regions. CONCLUSIONS: Low metabolic rates were confirmed in medial frontal cortical regions as well as in the basal ganglia, consistent with the importance of the cortical-striatal-thalamic pathways in schizophrenia. Loss of normal lateralization patterns was also observed on an exploratory basis. Correlations with negative symptoms and group differences were more prominent in medial than lateral frontal cortex, suggesting that medial regions may be more important in schizophrenic pathology.

Ligand dependence of cytochrome P450c17 protection against proteolytic inactivation: structural, methodological and functional implications.

Rate constants for the subtilisin-catalyzed proteolytic inactivation of cytochrome P450c17 (CYP17), the endoplasmic reticulum membrane-bound limiting enzyme of gonadal androgen synthesis, have been determined in the absence and presence of various CYP17 ligands and correlated with fractional enzyme saturation (Y). Extrapolation to Y = 1 reveals 15.1-, 4.0- and 7.4-fold enzyme stabilization with progesterone (substrate-type ligand), testosterone (product-type ligand) and ketoconazole (imidazole-type inhibitory ligand), respectively. Structural features of ligand accommodation can therefore be monitored by the susceptibility of target enzymes to proteolysis. It is further proposed that specific protection of a membrane protein by ligand binding during proteolytic digestion may assist in the purification of that protein. Evidence is finally presented that the gonadotropin-induced rapid CYP17 down-regulation is not promoted by an elevation of steroid hormone levels.

Quantitative instrumental measurement of tardive dyskinesia: a review.

In this paper we review currently available quantitative instrumental techniques for the assessment of tardive dyskinesia (TD). We discuss the advantages and disadvantages of the use of accelerometers, electromyography, force gauges, position transducers, and Doppler ultrasound from both a diagnostic and a utilitarian perspective. Data obtained using these techniques appear to correlate significantly with patient scores on clinical rating scales. In some cases, the use of these techniques has facilitated the detection of subclinical dyskinesia and helped to differentiate TD from other movement disorders. We believe that a review of these qualitative techniques will be of interest to the clinician, as well as to investigators involved in studying TD.

Partial reversal of the iminodipropionitrile-induced hyperkinetic syndrome in rats by alpha-tocopherol (vitamin E).

Rats were treated with the neurotoxin iminodipropionitrile (IDPN), which causes an irreversible movement disorder accompanied by axonal damage similar to that seen in vitamin E deficiency. Animals that received 2 g/kg vitamin E concurrently with 100 mg/kg IDPN for 10 days demonstrated a significantly reduced severity of IDPN-induced dyskinesia (as measured by vertical head movements) compared to animals that received IDPN alone. When animals were treated with 100 mg/kg IDPN for 10 days and then given either 2 g/kg vitamin E or an equivalent volume of sesame oil for 7 days, vitamin E produced a significant reduction in the severity of IDPN-induced dyskinesia. In both experiments, locomotor activity was unchanged by vitamin E. These data suggest a possible involvement of free radical formation in the neurotoxicity of IDPN.

A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia.

BACKGROUND: This study was designed to determine if vitamin E is effective in reducing the severity of abnormal movements in patients with tardive dyskinesia (TD). METHOD: Thirty-five patients completed a double-blind placebo-controlled parallel-group study of vitamin E. Seventeen of the patients were randomly assigned to receive 800 IU b.i.d. of vitamin E and 18 were assigned to placebo for 2 months. Twenty-nine patients had a diagnosis of schizophrenia and 6 of mood disorder. Patients were assessed using modified versions of the Abnormal Involuntary Movement Scale (mAIMS), Simpson-Angus Scale for extrapyramidal side effects, and Brief Psychiatric Rating Scale. Additionally, a subgroup of 23 patients were assessed using instrumental measurements of dyskinesia. RESULTS: There was a significant reduction of dyskinesia in the vitamin E group, but not the placebo group, on both the mAIMS and the instrumental assessments. The overall reduction in mAIMS in the active group was 24%, with 5 (29%) of 17 patients demonstrating greater than 33% reduction in score. There was a greater reduction in mean mAIMS score (35%) with vitamin E in the subgroup of patients with TD for 5 years or less compared with the reduction (11%) in patients with TD for greater than 5 years. No change was observed in parkinsonism. In the patients with schizophrenia, there was a reduction in positive symptoms after vitamin E. CONCLUSION: Vitamin E appears to be effective in reducing the severity of TD, especially in patients who have had TD for 5 years or less.

Gender-related clinical differences in older patients with schizophrenia.

BACKGROUND: Gender differences in the clinical presentation of young patients with schizophrenia have been well-documented, yet few studies have investigated gender-related clinical differences in older patients. Furthermore, the symptoms of late-onset schizophrenia have been described, but the interaction between gender and age at onset has not been examined. METHOD: In an older (46-85 years of age) outpatient sample, we assessed clinical characteristics of women and men with early-onset schizophrenia (N = 90) and late-onset schizophrenia (N = 34). Subjects did not differ with respect to age, education, ethnicity, severity of depression, daily neuroleptic dosage, subtype of schizophrenia, total score on the Mini-Mental State Examination, or severity of overall psychopathology. Diagnosis was made using the Structured Clinical Interview for the DSM-III-R or DSM-IV. RESULTS: A significantly greater proportion of women had late-onset schizophrenia (41% vs. 20%), and women overall had more severe positive psychotic symptoms. Although there was no overall gender difference in severity of negative psychotic symptoms, women with late onset had significantly less severe negative symptoms than men with early onset, men with late onset, and women with early onset. Furthermore, age at onset of schizophrenia was inversely correlated with severity of negative symptoms for women, but not for men. These results indicate that women overall may develop more severe positive symptoms than men, and that when women develop schizophrenia after age 45, they may suffer less severe negative symptoms than men or than women with earlier onset. Our results suggest that some of the clinical differences between late-onset and early-onset schizophrenia may relate to gender effects, and that there may be inherent differences in the clinical presentation of schizophrenia that are related to gender and gender by age at onset interactions. CONCLUSION: These differences may reflect the influence of sex hormones and menopause on the clinical presentation of schizophrenia or the possible existence of an "estrogen-related" form of schizophrenia in women with late-onset schizophrenia.

Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats.

Persistent tardive dyskinesia is a serious side effect of long-term treatment with neuroleptics. Although striatal pathologic changes are believed to underlie this potentially irreversible iatrogenic syndrome, the nature of the neuroleptic-induced neuropathology is unclear. In the present study, we treated rats with either vehicle or fluphenazine decanoate (5 mg/kg, IM) every 2 weeks for 4, 8 or 12 months. Four to nine weeks after the last injection, the animals were sacrificed and the density of cells in the central part of the striatum was measured with a computerized image-analysis system. The control and experimental animals did not differ in body weight with 4 and 8 months of treatment, but the rats treated with fluphenazine for 12 months had significantly lower body weights than comparable controls. Four months of neuroleptic use produced no significant neuropathologic changes. The animals treated with fluphenazine for 8 months had a significantly lower density of the large neurons. In the 12-month-treated group, there was no significant difference between the control and experimental animals, probably because of a 'floor effect': the density of the large neurons was significantly lower in the 12-month-treated compared to the 8-month-treated control rats.

Neuroleptic-induced striatal damage in rats: a study of antioxidant treatment using accelerometric and immunocytochemical methods.

RATIONALE: Investigators have postulated that neuroleptic medications may affect the motor system through the creation of free radicals. Also, structural brain changes related to oxidative damage may disrupt normal striatal function. OBJECTIVE: The goals of this study were to examine whether an antioxidant diet reduced the abnormal movements caused by long-term neuroleptic exposure and to examine structural effects within specific striatal regions in rats. METHODS: Rats were given a basal diet or a diet high in antioxidants for 4 months, and treated with 10 mg/kg fluphenazine decanoate or sesame seed oil IM every 2 weeks. At baseline and after treatment, head movements were quantified by accelerometry, and immunocytochemically stained cholinergic neurons in the ventrolateral, mediodorsal, and ventromedial regions of the striatum were quantified. RESULTS: Rats treated with fluphenazine had significantly lower neuron densities than those that did not receive antioxidants. Rats exposed to a diet consisting of antioxidants had significantly higher neuron densities than those that did not receive antioxidants in each of the three regions tested. Rats treated with fluphenazine had a greater increase in the number of accelerometric peaks recorded per minute compared with untreated animals. The increase in the number of accelerometric peaks recorded per minute was lower for animals exposed to antioxidant diets compared with unexposed animals. Lastly, there was a significant correlation between the accelerometric peak change score and cholinergic neuron density in all three regions. CONCLUSIONS: Our results suggest that long-term neuroleptic treatment is associated with an increase in head movements and a reduction in ChAT-stained striatal cholinergic neurons and that these abnormalities are reduced by antioxidants.

Reliability of an instrumental assessment of tardive dyskinesia: results from VA Cooperative Study #394.

Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training.