Olanzapine treatment for patients with schizophrenia and substance abuse.

The objective of this study was to evaluate the efficacy and safety of olanzapine in patients with schizophrenia and comorbid substance abuse disorders. Thirty patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder as well as criteria for substance abuse or substance dependence, were treated in a 12-month prospective, open-label trial of olanzapine. Patients were evaluated with multiple efficacy and safety measures at baseline and then monthly thereafter. Statistically significant improvement was noted in psychopathology, levels of hope, and safety measures. Seventy percent (n = 21) of the patients achieved early full substance abuse remission at the end of the study period, while 30% (n = 9) achieved early partial substance abuse remission. Our results indicate that olanzapine treatment improved psychopathology, increased hopefulness, and reduced antipsychotic-associated side effects. The benefits observed with olanzapine treatment may contribute to the patients' substance abuse remission.

Prolactin and antipsychotic medications: mechanism of action.

Until the introduction of the first atypical antipsychotic, clozapine, in 1975, hyperprolactinemia was assumed to be an inevitable consequence of treatment with any antipsychotic agent. Now we know that atypical antipsychotics such as clozapine, olanzapine, quetiapine, sertindole, and ziprasidone are not associated with significant prolactin increase. These new antipsychotics appear to spare dopamine blockade within the brain's tubero-infundibular tract, a dopamine pathway that also controls prolactin secretion. Since the release of prolactin is tonically inhibited by the hypothalamus, with dopamine acting as the prolactin release-inhibiting factor, any disruption of the connection between the hypothalamus and the pituitary gland is associated with hyperprolactinemia. Other factors that can increase prolactin secretion are also reviewed (e.g. estrogens, thyroid-releasing factor, vasoactive intestinal peptides, opioids, surgery, illness such as epilepsy or herpes zoster infection, and psychic or physical stress). Prolactin levels are at their highest 1-2 hours before waking, and early waking interrupts its secretion. The major effects of hyperprolactinemia in women are amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism, and increased long-term risk of osteoporosis. The effects in men are impotence, loss of libido, and hypospermatogenesis. Current data indicate that conventional antipsychotics, as well as high doses of risperidone (> 6 mg/day), increase prolactin levels to a range associated with sexual dysfunction in nonpsychiatric patients. The lack of prolactin elevation reported with the atypical antipsychotics is believed to be due to their much greater specificity, which results in less blockade of dopamine receptors in the tubero-infundibular pathway.

Structural asymmetries of the human brain and their disturbance in schizophrenia.

Asymmetries of the brain have been known about for at least a century, but they have been explored in detail only relatively recently. It has become clear that, although different asymmetries are common throughout the animal kingdom, they are most marked in the human brain. Disturbances in asymmetry are particularly striking in patients with schizophrenia and perhaps all psychotic illnesses, and may provide the neurological substrate for the etiology and clinical manifestations of the illness.

Management of chronic psychotic ambulatory outpatients.

The introduction of novel atypical antipsychotic medicines has raised new possibilities in the treatment of psychotic patients. In particular, the discovery of pharmacologic agents that may ameliorate the most stubborn positive and also negative symptoms without adding the burden of major side effects is revolutionizing treatment expectations. However, it is also becoming abundantly clear that successful treatment requires more than just the administration of a medicine. Treatment must also address the inner experiences of the patient, as well as the social and psychological handicaps that are associated with the illness. Some of the relatively neglected complications of using typical antipsychotic medicines include hyperprolactinemia and antipsychotics that may require concomitant treatment with anticholinergic agents, which themselves have an array of side effects. This article presents a detailed method for deciding when and how to use the new medications effectively and how to manage the transition from one medicine to another.

Premorbid educational attainment in schizophrenia: association with symptoms, functioning, and neurobehavioral measures.

BACKGROUND: The purpose of this study was to examine the association of educational attainment with phenomenology and neurobehavioral measures assessing brain structure and function in schizophrenia. METHODS: One hundred sixty-two patients with schizophrenia were divided into two groups on the basis of educational attainment: > or = 13 years of education was the cutoff between the high and low groups. The two education groups were compared on symptomatology, functioning, and subsamples on neuropsychological profile, brain volume by magnetic resonance imaging, and brain metabolism by fluorodeoxyglucose positron-emission tomography. RESULTS: The patients with more education had lower levels of psychotic symptomatology than their counterparts with less education. This was most evident for affective flattening, alogia, avolition, and bizarre behavior. The higher education group also had better ratings on premorbid adjustment, and the engagement and vocational factors of the Quality of Life Scale. Patients in the high education group also performed better on the neuropsychological battery. There were no brain volume differences or differences in brain metabolism between the two education groups. CONCLUSIONS: Education is an important indicator of premorbid function and is related to the clinical presentation of schizophrenia.

Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities.

OBJECTIVE: The planum temporale, the posterior superior surface of the superior temporal gyrus, is a highly lateralized brain structure involved with language. In schizophrenic patients the authors previously found consistent reversal of the normal left-larger-than-right asymmetry of planum temporale surface area. The original subjects plus new patients and comparison subjects participated in this effort to replicate and extend the prior study. METHOD: High-resolution magnetic resonance imaging of 28 schizophrenic patients and 32 group-matched normal subjects was performed. The authors measured planum temporale surface area, gray matter volume underlying the planum temporale, and gray matter thickness. Asymmetry indices for areas and volumes were calculated. RESULTS: Overall gray matter and total brain volume were not significantly smaller in the patients than in the comparison subjects. As previously reported, there was striking reversal of the normal asymmetry for planum temporale surface area in the male and female schizophrenic subjects. Bilaterally, gray matter volume beneath the planum temporale was smaller in the schizophrenic patients, and the gray matter thickness of the right planum temporale was only 50% of the comparison value. Volume of planum temporale gray matter did not show significant asymmetry in either group. CONCLUSIONS: This study extends the finding of reversed planum temporale surface area asymmetry in schizophrenic patients and clarifies its relationship to underlying gray matter volume. Although right planum temporale surface area is larger than normal in schizophrenia, gray matter volume is less than the comparison value; thus, gray matter thickness is substantially less than normal.

Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder.

Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia.

Schizophrenia throughout life: sex differences in severity and profile of symptoms.

BACKGROUND: The impact of aging and of gender has been examined in health and disease, but has received limited attention in schizophrenia. A lifespan perspective of gender differences can contribute to an understanding of clinical features and their underlying neurobiological processes. METHOD: A prospective sample of 272 patients with schizophrenia, divided into four age groups: < 35, 35-65, 65-80 and > 85, was assessed with standardized procedures to measure the composition and severity of symptoms. RESULTS: Aging was associated with increased severity of symptoms and gender differences were noted. Negative symptoms increased in severity, while some positive symptoms ameliorated with aging. Women were characterized by reduced negative symptoms, and this remained evident until the eighth decade. CONCLUSIONS: Aging and gender moderate the clinical features of schizophrenia in specific symptom clusters. These effects may give insight into neurobiological substrates of the illness.

Acute frontal lobe syndrome and dyscontrol associated with bilateral caudate nucleus infarctions.

BACKGROUND: A 67-year-old man presented with acute onset of spatial and temporal disorientation, memory loss and associated episodic dyscontrol. Investigations showed infarctions of both caudate nuclei. This patient presented a unique opportunity to study the relationship between the lesions, his behaviour, and neuropsychological testing. METHOD: Single case report. Investigations included interviews to determine cognitive impairment, i.e. WAIS-R, MMSE, and neurological examination. RESULTS: Extensive neuropsychological testing revealed severe impairment on tasks requiring planning, memory or abstract thought. These findings are very similar to those seen in Huntington's disease. CONCLUSIONS: A neurobiological hypothesis is proposed to account for his symptoms, and recent discoveries in the basic sciences used to inform his management.

Schizophrenia: a disease of heteromodal association cortex?

There is considerable evidence of disturbances of multiple brain areas in schizophrenia. The clinical features and findings from pathologic and neuro-imaging studies suggest primary involvement of a system of parallel distributed networks within the neocortex--the phylogenetically recent heteromodal association cortex (HASC). There is evidence that HASC is a family of higher-order parallel distributed networks of circuits, mediating complex representationally guided behaviors. We argue that HASC regions are especially involved in schizophrenia. Lesions of HASC in the disease are likely to be neurodevelopmental in origin (as evidenced by such examples as reversed planum temporale asymmetry) which have been identified by magnetic resonance imaging as specific regions of disproportionately reduced local gray matter volumes, and by neuropathologic examination as cellular migration disruptions. We believe the hypothesis of preferential heteromodal cortical abnormalities has heuristic value, and briefly indicate how it opens new avenues for investigating this debilitating condition.

Asymmetry of the planum temporale: methodological considerations and clinical associations.

Asymmetry of the planum temporale, a region on the posterosuperior surface of the temporal lobe involved in the production and comprehension of language, is a notable feature of the normal human brain. Several attempts have been made to measure it using both post-mortem and magnetic resonance imaging (MRI) methods, but previous approaches made inadequate allowance for the convoluted nature of the structure. The current study used rigorous criteria to define the planum and examined three separate approaches for its measurement on MRI scans. A method involving triangulation of the surface consistently gave larger values for the surface area of the planum, suggesting that this method takes account of the convoluted nature of the structure.

Reversal of asymmetry of the planum temporale in schizophrenia.

OBJECTIVE: The planum temporale is intimately involved in the generation and understanding of language and has been suggested to be a key area affected in schizophrenia. To explore temporal lobe abnormalities in schizophrenia, the authors measured the planum temporale, a normally asymmetric area lying on the superior part of the temporal lobe, in schizophrenic patients. METHOD: High-resolution magnetic resonance imaging (MRI) scans were obtained for 14 right-handed schizophrenic patients and 14 healthy comparison subjects individually matched for age, sex, handedness, race, and parental socioeconomic status. The surface area of the planum temporale was measured by using MRI reconstruction techniques. RESULTS: There was striking reversal of the normal asymmetry (left larger than right) in planum temporale surface area in 13 of the schizophrenic patients but in only two of the comparison subjects. However, Heschl's gyrus (primary sensory cortex), which served as an anatomically contiguous nonheteromodal cortical comparison region, showed no difference between the left and right sides in either group. Severity of thought disorder in the patients was related to asymmetry. CONCLUSIONS: This is a clear demonstration of a reversal of expected symmetry in the brains of right-handed schizophrenic patients, which involves a region of key importance in normal human behavior. The nature of the abnormality strongly suggests that schizophrenia is a neurodevelopmental disorder.

Absence of an angiogenic factor in large systemic arteriovenous malformations.

RATIONALE AND OBJECTIVES: Large symptomatic arteriovenous malformations (AVMs) are currently managed by a combination of surgery, embolization, and supportive measures. If patients with such lesions should have a circulating factor responsible for their growth and development, the evolution of a more rational therapy might be possible. METHODS: To explore this possibility, sera from 14 patients with high-flow systemic AVMs, widely distributed anatomically, were tested for the presence of a circulating growth factor using an assay already successfully used to isolate such a factor in diabetics with proliferative retinopathy. RESULTS: None of the patients tested positive for such a factor. CONCLUSIONS: This result, although negative, contributes to our knowledge of the biology of these uncommon but important lesions and leads us to conclude that, for the foreseeable future, embolization is likely to remain the most effective form of treatment for high-flow AVMs.

The influence of hypoglycaemic agents on the growth and metabolism of human endothelial cells.

Using human umbilical vein endothelial cells, and human microvascular endothelial cells from omental and subcutaneous fat obtained at laparotomy, we studied the effects of sulphonylureas and the biguanide metformin on endothelial cell proliferation, prostacyclin production, ecto-5'-nucleotidase activity, and von Willebrand factor release. Each drug produced a concentration-dependent proliferation of umbilical vein but not of microvascular endothelial cells. The stimulation of umbilical vein endothelial cell proliferation by sulphonylureas, but not by metformin, was serum- and insulin-dependent. Sulphonylureas and metformin had no effect on the proliferation of human dermal fibroblasts, smooth muscle cells derived from the umbilical artery, or 3T3 cells, until concentrations greater than 100 fold those found in vivo were reached, when there was inhibition of proliferation. These agents had no effect on prostacyclin or von Willebrand factor production, or on ecto-5'-nucleotidase activity, until high concentrations were used, at levels which also inhibited proliferation. The results suggest that the sulphonylureas and metformin, may, at concentrations found in vivo, induce changes in the turnover of endothelial cells from large vessels, but not of microvascular endothelial cells.

Diabetes is associated with a high incidence of endothelial-binding antibodies which do not correlate with retinopathy, von Willebrand factor, angiotensin-converting enzyme or C-reactive protein.

Increasing evidence implicates endothelial cell dysfunction in the development of diabetic microvascular disease, but its precise nature is elusive. This study sought to extend previous observations on the association between diabetes and the endothelial cell-derived glycoprotein von Willebrand factor (vWF), in a study of 777 diabetic patients. Compared with a mean of 1.07 +/- 0.18 iu/ml in a non-diabetic population, vWF was found to be elevated to 1.59 +/- 0.14 iu/ml in the whole sample, but particularly in those with retinopathy or microalbuminuria. It was studied whether such an elevation is part of an acute phase response, or is accompanied by other indicators of endothelial cell dysfunction. Plasma samples were examined for vWF, and serum for angiotensin converting enzyme (ACE), C-Reactive protein (CRP), IgG and IgM endothelial cell-binding antibodies (anti-EC Ig). A strong positive association was found (p less than 0.005) between the extent of elevation of vWF and the presence of diabetic retinopathy. ACE and CRP were rarely raised, and their levels did not correlate with either diabetic retinopathy or vWF levels. However, 52% of the patients had circulating anti-EC IgG or IgM, although their presence did not correlate with retinopathy, or with vWF, ACE or CRP. Thus diabetic retinopathy and probably nephropathy is associated with a specific but generalised disturbance of vascular endothelial cell function.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous blood flow responses in the forearms of Raynaud's patients induced by local cooling and intradermal injections of CGRP and histamine.

1. The cutaneous responses of the forearm to local cold exposure and intradermal injection of CGRP and other vasoactive mediators were compared in primary Raynaud's sufferers and normal volunteers. 2. Skin responses in the forearm were measured in terms of erythema reddening and skin blood flow. Visual responses were recorded by tracing and then area calculated by computerised planimetry. Skin blood flow was measured using a laser Doppler blood flow meter. 3. Cooling (5-6 degrees C for 2 min) of a 1 cm2 area of the forearm caused a localised reactive hyperaemia response in normal volunteers, measured using the last Doppler blood flow meter. The peak response in Raynaud's patients was significantly smaller than that of normal volunteers. 4. The cutaneous responses of Raynaud's patients and normal volunteers to intradermal injections of CGRP, histamine and PGE2 were not significantly different. 5. The results suggest that Raynaud's sufferers do not exhibit a diminished response to CGRP in the cutaneous microvasculature and can respond normally to histamine with an axon reflex mediated flare.

Long term effectiveness of photocoagulation for diabetic maculopathy.

The long term visual results of photocoagulation for diabetic maculopathy were determined in 128 eyes of 95 patients followed over ten years. The mean age of patients was 55.5 years and mean follow up time was 7 years. Ten year data were available on forty patients (62 eyes) and of the remainder the majority had died. Of those eyes initially with good vision (defined as 6/12 or better), 60% maintained this level of acuity at ten years and of those which deteriorated 50% became blind (defined as 6/60 or worse). A significantly greater proportion of eyes with exudative maculopathy (48%) had good final vision compared to eyes with oedematous and ischaemic maculopathy (26%).