Exercises for mechanical neck disorders: A Cochrane review update.

BACKGROUND: Neck pain (NP) is disabling and costly. OBJECTIVES: To assess the effectiveness of exercise on pain, disability, function, patient satisfaction, quality of life (QoL) and global perceived effect (GPE) in adults with NP. METHODS: We searched computerised databases up to May 2014 for randomized controlled trials (RCTs) comparing exercise to a control in adults with NP with/without cervicogenic headache (CGH) or radiculopathy. Two reviewers independently conducted selection, data abstraction and assessed risk of bias. Meta-analyses were performed to establish pooled standardised mean differences (SMDp). The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) was used to summarise the body of evidence. MAIN RESULTS: The following exercises (27 trials) were supported by 'Moderate GRADE' evidence: For chronic NP, 1) cervico-scapulothoracic and upper extremity (UE) strengthening for moderate to large pain reduction immediately post treatment (IP) and at short-term (ST) follow-up; 2) scapulothoracic and UE endurance training for a small pain reduction (IP/ST); 3) cervical, shoulder and scapulothoracic strengthening and stretching exercise for a small to large pain reduction in the long-term (LT) (SMDp -0.45 [95%CI: -0.72 to -0.18]) and function improvement; 4) cervico-scapulothoracic strengthening/stabilisation exercises for pain and function at intermediate-term (IT) (SMDp -14.90 [95%CI: -22.40 to -7.39]). 5) mindfulness exercises (Qigong) for minor improved function but not GPE (ST). For chronic CGH, cervico-scapulothoracic strengthening and endurance exercises including pressure biofeedback for small/moderate improvement of pain, function and GPE (IP/LT). AUTHORS' CONCLUSIONS: Specific strengthening exercises of the neck, scapulothoracic and shoulder for chronic NP and chronic CGH are beneficial. Future research should explore optimal dosage.

Neuronal correlates of appetite regulation in patients with schizophrenia: is there a basis for future appetite dysfunction?

BACKGROUND: Given the undesired metabolic side effects of atypical antipsychotic medication it is important to understand the neuronal basis related to processing of appetite regulation in patients affected by schizophrenia. METHODS: Here we used functional magnetic resonance imaging (fMRI) to assess brain activity in response to food cues and neutral stimuli in twenty patients with schizophrenia and eleven healthy individuals. In addition to clinical and dietary habits assessments, we collected, in patients, measurements of fasting glucose, ghrelin, leptin, insulin, prolactin and lipids blood concentration and we correlated the cerebral activity with clinical and metabolic measures. RESULTS: Both groups engaged a common neuronal network while processing food cues, which included the left insula, primary sensorimotor areas, and inferior temporal and parietal cortices. Cerebral responses to appetitive stimuli in thalamus, parahippocampus and middle frontal gyri were specific only to schizophrenic patients, with parahippocampal activity related to hunger state and increasing linearly over time. Antipsychotic medication dosage correlated positively with a cognitive measure reflecting food cravings, whereas the severity of the disease correlated negatively with a cognitive measure indicating dietary restraint in eating habits. These cognitive variables correlated, in turn, with parahippocampal and thalamic neuronal activities, respectively. CONCLUSIONS: We identified a specific neural substrate underlying cognitive processing of appetitive stimuli in schizophrenia, which may contribute to appetite dysfunction via perturbations in processing of homeostatic signals in relation to external stimuli. Our results also suggest that both antipsychotic medication and the disease severity per se could amplify these effects, via different mechanisms and neuronal networks.

Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment.

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.

Migration of bisphenol A from plastic baby bottles, baby bottle liners and reusable polycarbonate drinking bottles.

Human exposure to bisphenol A (BPA) has recently received special attention. It has been shown that exposure to BPA may occur through the consumption of beverages or foods that have been in contact with polycarbonate (PC) plastic containers or epoxy resins in food packaging. A BPA migration study was conducted using a variety of plastic containers, including polycarbonate baby bottles, non-PC baby bottles, baby bottle liners, and reusable PC drinking bottles. Water was used to simulate migration into aqueous and acidic foods; 10% ethanol solution to simulate migration to low- and high-alcoholic foods; and 50% ethanol solution to simulate migration to fatty foods. By combining solid-phase extraction, BPA derivatization and analysis by GC-EI/MS/MS, a very low detection limit at the ng l(-1) level was obtained. Migration of BPA at 40 degrees C ranged from 0.11 microg l(-1) in water incubated for 8 h to 2.39 microg l(-1) in 50% ethanol incubated for 240 h. Residual BPA leaching from PC bottles increased with temperature and incubation time. In comparison with the migration observed from PC bottles, non-PC baby bottles and baby bottle liners showed only trace levels of BPA. Tests for leachable lead and cadmium were also conducted on glass baby bottles since these represent a potential alternative to plastic bottles. No detectable lead or cadmium was found to leach from the glass. This study indicated that non-PC plastic baby bottles, baby bottle liners and glass baby bottles might be good alternatives for polycarbonate bottles.

[Clozapine and pregnancy]. / Clozapine et grossesse.

This article reviews the relations between clozapine and pregnancy. Six case reports are identified in the literature of pregnant patients who received clozapine. Novartis at Basle, Switzerland, through its pharmacovigilance and epidemiology, service, has data on nearly 200 cases summarized in this article. We also describe the case of a patient with paranoid schizophrenia who was hospitalized 10 times between the age of 22 to 32. She received clozapine when she was 29 years old and, with a daily dosage of 350 mg, she became asymptomatic. At the age of 33 and 37, she became pregnant and continued clozapine during her 2 pregnancies. During her first pregnancy, she received insulin due to gestational diabetes associated with a body weight mass (BWM) of 30.4 (N = 20 to 25). During her second pregnancy, the BWM was 23.7 and she did not develop diabetes. She delivered at term 2 daughters who are at the time of this report 5 and 3 years old. The two girls are doing well and have no developmental delay. Psychotic symptoms exacerbation: the plasma concentration of clozapine diminishes during pregnancy due to a higher hepatic metabolism and distribution volume. Monitoring plasma concentration of clozapine can help to adjust its dosage. In case of psychotic symptoms exacerbation, the following can be recommended: 1) Increase the clozapine dosage; 2) Add a classic antipsychotic like perphenazine, trifluoperazine or haloperidol. Diabetes: obesity, glucose intolerance or a family history of diabetes are risk factors to develop gestational diabetes. The follow-up of patients, who take an atypical antipsychotic, should include constant monitoring of the blood glucose or Hb1A and lipid dosages. Complications at labor: Clozapine increases the secretion of oxytocine and the contraction of the uterine muscle. But, no studies can explain how clozapine affects the labor exactly. Some case studies report use of forceps, vacuum or cesarean. CONVULSIONS: Stoner (1997) described neonatal convulsions 8 days after birth. The mother was receiving 350 mg of clozapine, but also lorazepam and haloperidol during her pregnancy. The newborn withdrawal of lorazepam can increase the risk of convulsions and also haloperidol can diminish the convulsion threshold. Floppy infant syndrome: in the case described by Dimichele (1996), the mother received a daily dosage of 300 mg of clozapine and 2.5 mg of lorazepam 3 to 5 times a day. This can explain hypotonia. Stoner (1997) reports a second case where a mother, who received 600 mg of clozapine during pregnancy, gave birth to a child who had no convulsions neither hypotonia. DEVELOPMENT: The cases described concerning studies of children until age 2 to 3 years by Stoner (1997) and Dickson (1998) and until 6 years old by Barnas (1994), do not mention any developmental problem, similar to the two daughters of our patient. The pharmacovigilance service of Novarits reports 6% of malformations. But these reports must be considered with caution since they represent only the pregnancies reported spontaneously to the pharmaceutical company. This is only a portion of all pregnancies associated with clozapine. CONCLUSION: No specific risks for the mother and children can be attributed to the use of clozapine during pregnancy. However, the plasma concentration of clozapine is higher in the fetus compared to the mother (Barnas, 1994); therefore, a minimal dosage should be used. Since clozapine is present in the maternal milk, breast feeding should be avoided. The advantages to use clozapine during pregnancy must exceed the risks. It is justified to continue the use of this medication even if data on classic antipsychotics (e.g.: haloperidol) are more extensive. Because the risk of psychotic exacerbation is higher, the substitution of clozapine is not recommended. The psychosocial support and the obstetrical follow-up must be intensive too. An institutional pharmacovigilance service should complement the one provided by the industry. Also, further case-control and cohort studies are essential to better estimate the long-term risks.

DRD3 and DAT1 genes in schizophrenia: an association study.

OBJECTIVE: To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS: a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS: No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION: These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.

Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia.

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better long-term outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome.

Analysis of 14 CAG repeat-containing genes in schizophrenia.

Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.

[Atypical neuroleptics and selective attention]. / Neuroleptiques atypiques et attention sélective.

GOALS: The aim of this study was to examine selective attention in patients with chronic and refractory schizophrenia who had been exposed for six months to atypical neuroleptic medications: risperidone or clozapine. METHOD: 17 patients satisfying DSM III-R criteria for schizophrenia were assessed according to BPRS and PANSS and abnormal involuntary movements to ESRS. Selective attention tasks were performed before treatment with risperidone or clozapine and at two times during the treatment (6 weeks, T1, and 24 weeks, T2). Patients' performance data were compared to data from a group of general population at T1. Selective attention refers to the ability to discriminate relevant information from irrelevant one. This was measured by a visual search task. Subjects had to search for a target specified by a conjunction of features (color and shape). The target was a black X, while the distracters were white X's, black O's and white O's. The stimuli were displayed on a Macintosh SE computer. A two-button response box was used for response production and the experiment was run in a dimly lit room. A white-fixation stimulus was shown at the center of the display screen between trials. The number of stimuli displayed on a single trial was 1, 4, 7 or 10. The median RTs and error rates of subjects were computed for each factor (target presence and number of stimuli). RESULTS: A Group X Number of items X Presence of target ANOVA applied on median correct RTs revealed a significant Group X Presence interaction [F(1,176) = 60.433, p < .0001]. Performances improved with the time (F2, p < .01). Correlations were found between positive score on PANSS and performance on selective attention (r39 = -.391). CONCLUSION: Atypical neuroleptic do not have a deleterious effect on selective attention but a favorable effect on the schizophrenic patients' performance.

T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability.

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.

Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia.

Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.

Polyglutamine-containing proteins in schizophrenia.

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.

[From symptomatology to problem-solving : an integrated approach for people with schizophrenia.]. / De la symptomatologie à la résolution de problèmes : approche intégrée pour les personnes atteintes de schizophrénie.

People with schizophrenia experience difficulties in adapting and managing problematical situations of daily life thus diminishing their social coping skills. Several components such as cognitive deficits and biases associated with symptomatology disrupt their problem-solving skills. In social rehabilitation, it is essential to take into account all characteristics and offer an integrated approach. This article presents an approach to problem-solving skills with a contemporary knowledge of schizophrenia. The functionning of the Clinique Jeunes Adultes of the Louis-H. Lafontaine Hospital is presented and serves as a reference.

Patients versus rehabilitation practitioners: a comparison of assessments of needs for care.

OBJECTIVE: A group of 47 young adults suffering from schizophrenia was interviewed to garner their views on their needs for care. METHOD: Three members of a specialized multidisciplinary rehabilitation team, who had been caring for these patients, on average, for the past 4 years, completed a questionnaire to assess the needs for care of these individuals. Patient and staff assessments were then compared. RESULTS: Patients and staff do not share similar views on the presence of clinical and social problems. Further analyses of the perceived importance of living-skills deficits, the perceived difficulties in dealing with these, and the recent developments in rehabilitation practices challenge whether patient-staff consensus is indeed essential for rehabilitation. CONCLUSION: We propose that staff should listen to patients' points of view more carefully, especially in the areas of work, studies, and independent living.

Patterns of geographic mobility of persons with AIDS in Canada from time of AIDS index diagnosis to death.

OBJECTIVE: To characterize migration patterns of persons with AIDS in Canada during the period from AIDS diagnosis to death. DESIGN: Descriptive, population-based study. SETTING: Canada. PATIENTS: Canada's AIDS Case Reporting Surveillance System (ACRSS) was linked to deaths in the Canadian Mortality Data Base (CMDB). Probabilistic linkage was based on initials, date of birth, date of death, birthplace, and location at diagnosis and at death. Analysis was restricted to AIDS cases reported from Jan. 1, 1982, to Sept. 30, 1994, and to deaths reported from Jan. 1, 1982, to Dec. 31, 1992. MAIN OUTCOME MEASURES: Change in usual place of residence; migration rates by region and community size. RESULTS: A total of 5755 AIDS cases recorded in the ACRSS were linked to deaths in the CMDB. Of these linked cases, 5366 (93%) included information on province or territory of usual residence or community size. A total of 160 (3.0%) persons with AIDS changed their province or territory of residence between the time of their AIDS diagnosis and death. Multivariate analysis indicated that those who changed residences between AIDS index diagnosis and death were more likely than other persons with AIDS to live in provinces other than British Columbia, Ontario and Quebec (p < 0.001), to be diagnosed earlier (p = 0.004), to be younger (p < 0.001) and to be gay or bisexual (p = 0.042). CONCLUSIONS: Our analysis revealed that only a small proportion of persons changed their residence between AIDS diagnosis and death. Geographic mobility was the greatest among persons with AIDS residing outside of the regions where the overwhelming majority of persons with AIDS in this country reside.

Differential effects of D2- and D4-blocking neuroleptics on the procedural learning of schizophrenic patients.

OBJECTIVE: To illustrate the differential effects of D2- and D4-blocking neuroleptics on the procedural learning of patients with schizophrenia. METHOD: Twenty-nine schizophrenic patients were divided into 3 groups according to their pharmacological treatment: 1) drug naive, 2) haloperidol, and 3) clozapine. They were all assessed on clinical and procedural measures, the latter being the mirror drawing task. RESULTS: All groups showed progressive learning over the successive trials, and drug-naive patients performed better than the other groups. Patients in the haloperidol group showed many fluctuations over trials, suggesting difficulty in the progressive automation of the task. Such fluctuations did not occur in the clozapine group, but performances per se were worse than in the other groups during the learning trials. Automation of the task occurred at the same point (second block of trials) for all groups. CONCLUSION: These results suggest that D2- and D4-blocking neuroleptics do not similarly affect striatal dependent procedural learning in schizophrenia.

[Strategies for coping in schizophrenia]. / Stratégies de coping la schizophrénie.

Few studies have documented how schizophrenic patients perceived their needs and which coping skills they have spontaneously developed. All 48 patients of the Louis-H. Lafontaine Young Adults Clinic, a specialised schizophrenia clinic in Montreal, were invited to complete the Task Motivation and Problem Appraisal in Long Term Psychiatric Patients questionnaire. Our study utilised a descriptive approach and a classification of patient's reported problems and their coping skills. A panel of researchers and clinical staff then regrouped patient's perceived problems into four categories: symptoms, coping strategies, organisation of daily activities and interpersonal contacts. The main coping strategies utilised by these young patients are confrontation (52%) emotion-centered coping (57%). Clinical applications can be drawn from paying attention to the reports of schizophrenic patients. For example, rehabilitation activities can be developed which cater to their perceived needs. Because of frontal lobe hypoactivity, which make cognitive appreciation more difficult, their coping strategies should be diversified. Patients suffering from negative symptoms of schizophrenia mainly attempt to modify emotional impact, until they have discovered a way of confronting deficit symptoms. Better motivation to therapeutic programmes would result from paying attention to their perspectives.

Clozapine: current status and role in the pharmacotherapy of schizophrenia.

OBJECTIVE: This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia. METHOD: Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options. RESULTS: Clozapine represents the prototype of "atypical" neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning. CONCLUSION: Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics.