The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover study.
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Adult↗
Biomedical subjects
Robert R Conley
Publications and source records attributed to Robert R Conley.
Interstitial cells of the white matter in the dorsolateral prefrontal cortex in deficit and nondeficit schizophrenia.
An increased density of neurons in the white matter of the neocortex has been found in schizophrenia, and the original reports suggested this abnormality was restricted to a subgroup of patients. In a study of the inferior parietal cortex, we found that deficit schizophrenia subjects, but not nondeficit subjects, had an increased density of ICWMs. We extended that finding by comparing the density of microtubule-associated protein 2-immunoreactive ICWMs in deficit schizophrenia (N = 3), nondeficit schizophrenia (N = 4), and control (N = 5) subjects, using postmortem tissue from the dorsolateral prefrontal cortex (Brodmann area 46). The deficit group differed significantly from the other two groups; the respective mean (SD) density values for the deficit, nondeficit, and control groups were 1.27 (.10),.53 (.39), and.76 (.20) cells per 10-6 cubic microns. These group differences provide further evidence that deficit and nondeficit schizophrenia differ in their pathophysiology.
Adult↗
Deaths from diabetic ketoacidosis after long-term clozapine treatment.
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Adult↗
Clozapine treatment in patients with prior substance abuse.
OBJECTIVE: This study examined outcomes following discharge on clozapine for treatment-resistant schizophrenia patients with and without diagnosed substance abuse histories. METHODS: Those discharged on clozapine from a research unit between April 1991 and March 1996 were followed with respect to hospitalization status. Of the treatment-resistant patients with schizophrenia, 19 were diagnosed as individuals with substance abuse, while 26 patients had no history of abuse. Patients were openly treated with clozapine and were included in the study if they were stabilized and discharged on the medication. RESULTS: Patients who had histories of abuse exhibited a better treatment response and a lower total Brief Psychiatric Rating Scale (BPRS) score at discharge, compared with the non-substance abuse group. One-year readmission rates were 21% and 23% in patients with and without prior substance abuse histories, respectively (P = ns). CONCLUSIONS: Clozapine may be a therapeutic option for the dually diagnosed population and may offer benefits to patients with schizophrenia who have a history of substance abuse.
Adult↗
Six-month review of weight and metabolic parameters in patients receiving clozapine, risperidone, olanzapine, or quetiapine.
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Adult↗
Circumstances of suicide among individuals with schizophrenia.
Very little is known about the circumstances surrounding suicides in people with schizophrenia. Between September 1989 and August 1998, 15 and 100 suicide victims with and without schizophrenia, respectively, were examined from the Maryland Brain Collection (MBC). Next-of-kin interview and medical record review following death collected demographic and clinical characteristics, family history, psychiatric symptoms, and variables surrounding the suicide. Individuals with schizophrenia exhibited significantly more lifetime depressive symptoms than those without schizophrenia. Jumping from a height was the most frequently used method among people with schizophrenia (40%), whereas gunshot wounds were most common among persons without schizophrenia (37%). A trend was noted for a smaller proportion of those with schizophrenia (20%) to plan the suicide, compared to 47% of those without the disorder. Suicide in schizophrenia is a significant clinical problem; thus, prior suicidal activity and depressive symptoms should be addressed because opportunities to intervene immediately before the act are limited.
Adult↗
Novel factor-based symptom scores in treatment resistant schizophrenia: implications for clinical trials.
To study the factor structure of symptoms in patients with treatment resistant schizophrenia and whether it is altered by treatment, we analyzed ratings on the Brief Psychiatric Rating Scale (BPRS) from two independent groups of patients with treatment resistant schizophrenia. With confirmatory factor analysis of pre-clozapine BPRS scores in 1074 patients in an administrative data base, the Clozapine Authorization and Monitoring Program (CAMP), we assessed the fit of published factor models and developed a better-fitting model. Model fit was validated in an independent group of 197 research unit participants. Stability of model fit six months post-clozapine was assessed in 834 CAMP patients. A new 4-factor model (negative symptoms, reality distortion, disorganization, and anxiety/depression) had better fit in both data sets than two commonly used factor models, and also fit better post-clozapine. We recommend these four factor scores as clinical trial outcomes in patients with treatment resistant schizophrenia.
Adolescent↗
mRNA and protein expression of selective alpha subunits of G proteins are abnormal in prefrontal cortex of suicide victims.
The present investigation was undertaken to examine whether there is an abnormality in the expression of alpha and beta gamma subunits of G proteins both at the transcriptional and translational level in postmortem brain of adult and teenage suicide subjects and whether these abnormalities are related to mental disorders or suicide per se. In addition, an attempt has been made to investigate whether these abnormalities are similar or dissimilar in teenage and adult suicide, because the etiology of teenage suicide may be different than that of adults.A significant decrease in both mRNA and protein levels of G(i2)alpha and G(O)alpha and a significant increase in levels of G(s)alpha(-S) were observed in prefrontal cortex of suicide subjects (n = 43) compared with non-psychiatric control subjects (n = 38). When subjects were grouped according to age, a significantly decreased expression of G(i2)alpha and G(O)alpha and significantly increased expression of G(s)alpha(-S) were observed in adult suicide subjects (age > or = 20 yrs; n = 20) as compared with age-matched controls (n = 27). These changes were present in all adult suicide subjects regardless of psychiatric diagnosis. On the other hand, although there were no significant differences in any alpha or beta gamma subunits in teenage suicide subjects (age < or = 19 yrs; n = 16) when compared with matched control subjects (n = 18); however, mRNA and protein levels of G(i2)alpha and G(O)alpha were significantly decreased and of G(s)alpha(-S) were significantly increased only in those teenage suicide subjects who had a history of mental illness (n = 11). Our results suggest that there are defects in the expression of selective G protein alpha subunits in prefrontal cortex of adult and teenage suicide subjects, which appear to be related to mental disorders.
Adolescent↗
[(3)H]cAMP binding sites and protein kinase a activity in the prefrontal cortex of suicide victims.
OBJECTIVE: The cAMP-dependent enzyme protein kinase A phosphorylates intracellular proteins upon activation and thereby plays a major role in mediating various physiological functions in the brain. To examine the role of this enzyme in suicidal behavior, the authors examined the catalytic and regulatory activities of protein kinase A in the postmortem brain of suicide victims. METHOD: Brain tissues were collected from 17 suicide victims and 17 nonpsychiatric comparison subjects. Regulatory activity was determined by examining [(3)H]cAMP binding to protein kinase A, while catalytic activity was determined by enzymatic assay in the presence (total activity) and the absence (endogenous activity) of cAMP in the membrane and cytosol fractions of the prefrontal cortex. RESULTS: The number (B(max)) of [(3)H]cAMP binding sites to protein kinase A was significantly lower in the suicide victims without any changes in affinity in either the membrane or cytosol fractions of the prefrontal cortex. Further, significantly less protein kinase A activity, both in the presence and the absence of cAMP, was seen in the membrane and cytosol fractions of the prefrontal cortex of suicide victims; however, the difference in total protein kinase A activity was much more pronounced. CONCLUSIONS: The results suggest that cAMP binding to the regulatory subunits of protein kinase A, as well as the phosphotransfer catalytic activity of protein kinase A, are lower in the prefrontal cortex of suicide victims than in nonpsychiatric comparison subjects, which may be of clinical relevance in the pathophysiology of suicidal behavior.
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Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims.
OBJECTIVE: Abnormalities of serotonin (5-HT) receptor subtypes have been observed in the postmortem brains of adult suicide victims; however, their role in teenage suicide is unexplored. The authors examined whether 5-HT(2A) receptor subtypes are altered in the postmortem brains of teenage suicide victims. METHOD: Levels of 5-HT(2A) receptors were determined through examination of [(125)I] LSD binding, protein expression (by use of Western blotting with a specific 5-HT(2A) receptor antibody), and mRNA (by means of quantitative reverse transcription polymerase chain reaction) in the prefrontal cortex, hippocampus, and nucleus accumbens of 15 teenage suicide victims and 15 normal matched teenage subjects. The cellular localization of the 5-HT(2A) receptors was determined by means of gold immunolabeling. RESULTS: The authors observed significantly higher [(125)I]LSD binding in the prefrontal cortex and greater protein expression and mRNA levels in the prefrontal cortex and hippocampus but not in the nucleus accumbens of suicide victims, compared with normal subjects. Greater protein expression was localized on pyramidal cells in cortical layer V but not in other cortical layers or in the surrounding neuropil of the prefrontal cortex of teenage suicide victims. CONCLUSIONS: The evidence indicates higher levels of 5-HT(2A) receptor, protein, and mRNA expression in the prefrontal cortex and hippocampus, which have been implicated in emotion, stress, and cognition. There was no higher level in the nucleus accumbens, which has been implicated in drug dependence and craving. Our findings suggest that a higher level of 5-HT(2A) receptors may be one of the neurobiological abnormalities associated with teenage suicide.
Adolescent↗
Current status of antipsychotic treatment.
With the use of chlorpromazine and other traditional antipsychotics for psychosis, it was soon discovered that the antipsychotic efficacy of this class of medications was closely associated with their ability to block dopamine D(2) receptors in the brain. This prompted the hypothesis that the etiology of schizophrenia and other psychotic illnesses might be caused by a dysregulation of dopamine. This hypothesis, that the dopamine system explains schizophrenia symptoms, however, is far from complete and the treatment with conventional antipsychotic medications is far from ideal. There has been a great deal of speculation regarding the role of serotonin receptor antagonism in regards to antipsychotic effects. The second generation antipsychotics (SGAs), clozapine, risperidone, olanzapine, quetiapine and ziprasidone all have relatively high serotonin to dopamine binding ratios. Serotonin receptor binding may be important to these drugs' actions, possibly by stimulating dopamine activity in mesocortical pathways. Yet, while the mechanism of action of SGAs as a group remain unsolved, it is important to note that the SGAs offer many clinical benefits to treatment as compared to traditional antipsychotics and are quickly emerging as first-line therapy for schizophrenia. In addition to lower rates of EPS and tardive dyskinesia, other benefits to treatment with this class of antipsychotics include better treatment of negative symptoms, better compliance, possible benefits for cognitive impairments, lower rates of relapse and rehospitalization, and more cost-effective therapy. Within the class of SGAs, however, differences exist both in efficacy and side effects and these will be described. Optimization of treatment and understanding the exact mechanism of action of current antipsychotic medications will help pave the way for new drug targets in the future.
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Cardiovascular disease in relation to weight in deceased persons with schizophrenia.
This study evaluated body mass index, body surface area, subcutaneous fat tissue, and coronary atherosclerosis by autopsy reports for people with schizophrenia who were deceased to evaluate the presence of cardiac atherosclerosis and its association with body weight. Included in the study were autopsy reports for 134 people with schizophrenia and 134 matched normal subjects who had died between January 1990 and December 2000 and whose family had donated brain tissue to Maryland Brain Collection. Cause of death due to cardiovascular disease was observed for 45.7% of people with schizophrenia and 42.3% of the control group (P = NS). Body weight, body mass index, body surface area, and subcutaneous fat were not significantly different between the 2 groups; however, a larger proportion of the schizophrenia group had high (33.3%) and low (20.9%) percentile body weight compared with controls (27.7% vs 10.0%). People with schizophrenia who were underweight had higher rates of cardiac death than the controls (37.7% vs 13%) (chi(2) = 5.79, P = .01); however, no difference was noted in the number of coronary arteries occluded. Twenty-three (48.9%) of 47 of the controls with abnormally high subcutaneous fat showed cardiac atherosclerosis, whereas only 15 (33.3%) of 45 of the schizophrenia group with abnormally high subcutaneous fat had atherosclerosis (P = NS). Overall, the percentage of deaths due to cardiovascular disease was not higher in people with schizophrenia; however, in normal controls, cardiovascular disease appears to be related more to weight than in people with schizophrenia. This may be related to intrinsic metabolic differences associated with schizophrenia, lifestyle differences, or effects of antipsychotic medications. Nonetheless, our study suggests that efforts for the prevention of coronary atherosclerosis in schizophrenia patients should go beyond weight control to target multiple risk factors such as smoking, dyslipidemia, and cardiac side effect of antipsychotic medications.
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Lifetime psychiatric symptoms in persons with schizophrenia who died by suicide compared to other means of death.
The focus of this report is to compare the psychiatric symptomatology of individuals with schizophrenia who have died by suicide to those who have died by other means of death. This study includes individuals with a diagnosis of schizophrenia whose families donated their brain tissue to the Maryland Brain Collection between September 1989 and August 1998. The psychological autopsy method was used to assess the deceased individual's demographic and clinical characteristics, psychiatric symptoms and history of suicidal thoughts and attempts. Ninety-seven individuals with schizophrenia were identified for this study. Fifteen had committed suicide, while the remaining 82 died from other causes. Thoughts of suicide and previous suicide attempts were more frequent among the group that died from suicide (93% compared to 26%) (p < 0.0001). Suicide victims had a higher rate of depressive symptoms and were twice as likely to have a depressed mood. The incidence of thoughts of dying was 60% compared to 20% in those who did not commit suicide (p = 0.002). Loss of interest was reported to occur in 20% in the suicide group compared to 4% in the group of individuals that died from other causes (p = 0.05). Victims of suicide also had higher rates of positive symptoms throughout their lifetime including thought control, flight of ideas, and loose associations. Suicide is one of the leading cause of premature death in individuals with schizophrenia and identification of risk factors is of great importance. Individuals who die by suicide experience higher rates of depressive symptoms, suicidal thoughts and positive symptoms during their life.
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Altered expression and phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in postmortem brain of suicide victims with or without depression.
Myristoylated alanine-rich C kinase substrate (MARCKS), an acidic, heat-stable protein, is involved in important physiological functions such as neurotransmitter release and re-uptake. It is also a substrate for phosphorylation by protein kinase C (PKC) and has been shown to play a role in the pathophysiology of mood disorders. In this study, protein and mRNA expression of MARCKS as well as phosphorylation of MARCKS were determined in the prefrontal cortex (PFC) and hippocampus of postmortem brain obtained from suicide victims, with or without depression, and normal control subjects. There were no significant differences in mRNA and protein levels of MARCKS between suicide subjects and controls. However, protein levels of MARCKS were significantly increased in the membrane but not in cytosol fraction of PFC and hippocampus obtained from depressed suicide subjects as compared to normal controls. When PKC-mediated MARCKS phosphorylation was determined, it was observed that MARCKS phosphorylation was significantly decreased in the membrane fraction of PFC and hippocampus obtained from total suicide subjects as well as depressed and non-depressed suicide subjects compared with control population. Although the mechanism of such alterations in MARCKS in depressed and non-depressed suicide subjects is not clear, results of the present study indicate that an increase in membrane MARCKS is associated with depressed suicide victims and a decrease in MARCKS phosphorylation may be a common feature of suicide victims independent of diagnosis.
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Adverse effects and laboratory parameters of high-dose olanzapine vs. clozapine in treatment-resistant schizophrenia.
Patients with treatment-resistant schizophrenia pose a major challenge to caregivers since only clozapine is documented as having superior efficacy in this population. Although olanzapine is similar to clozapine in structure and receptor profile, it has not been proven to have superior efficacy for this patient group. Nonetheless, olanzapine is being increasingly used in higher doses as clinicians attempt to find a more effective and tolerable therapy for refractory patients. Furthermore, there are little data comparing olanzapine and clozapine in this population. Thirteen patients participated in a randomized double-blind 16-week crossover study of clozapine therapy (450 mg/day) compared to high doses of olanzapine (50 mg/day). No patients on olanzapine responded while 20% responded to clozapine treatment. Olanzapine patients tended to experience higher rates of anticholinergic effects such as dry mouth (80 vs. 20%) and blurry vision (40 vs. 0%). Clozapine-treated patients had higher rates of sialorrhea (80 vs. 10%), sweating (50 vs. 10%), dyspepsia (70 vs. 30%), and lethargy (90 vs. 60%). Neither treatment was associated with significant akathisia. Liver enzyme elevation and lipids were higher with clozapine treatment. Mean weight gain in the initial 8 weeks was 3.4 kg for olanzapine and 1.2 kg for clozapine. High doses of olanzapine during 8 weeks of treatment did not increase lipids and liver enzymes like clozapine did. Olanzapine at 50 mg/day may be associated with more anticholinergic effects and weight gain than clozapine.
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Cortisol response to buspirone in extended abstinent alcoholics.
We evaluated cortisol response to buspirone in extended abstinent alcoholic patients to determine 5-HT1A receptor sensitivity in alcoholism. Alcoholic patients were inpatients with an extended abstinent period of at least 3 months. Alcoholics had a significantly lower cortisol level than did the normal controls from 60 min through to 150 min after administration of 30 mg buspirone. Our results show that cortisol response to buspirone was significantly decreased in alcoholic patients compared to normal controls, reflecting decreased 5-HT1A receptor sensitivity.
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Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone.
Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.
Antipsychotic Agents↗
Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia.
This 12-week, double-blind study evaluated the effectiveness of risperidone (4 mg/day), quetiapine (400 mg/day), or fluphenazine (12.5 mg/day) in a stringently defined treatment-resistant population of people with schizophrenia. No differences were noted in total Brief Psychiatric Rating Scale (BPRS) or Clinical Global Impression scores among the drug groups (n = 38). More subjects tended to complete the study on risperidone (69%) or quetiapine (58%) than those treated with fluphenazine (31%; P value not significant). Eighty-nine percent of those who discontinued on fluphenazine (8 of 9) were due to lack of efficacy. Discontinuation due to adverse effects was low, with only 2 subjects (both on quetiapine) stopping due to side effects. Three of 13 risperidone-treated subjects (23%) and 3 of 12 quetiapine-treated subjects (25%) met response criteria (decrease of 20% of total BPRS score), whereas 2 of 13 subjects (15%) responded to fluphenazine. Side effect occurrence was similar among drug groups and EPS ratings on the Simpson Angus Scale improved in all drug groups (quetiapine, 1.64; risperidone, 1.30; fluphenazine, 0.69; P value not significant). Despite the newer class of second-generation antipsychotic medications, this treatment-resistant population remains difficult to treat. Many people have only minimal to modest improvements with antipsychotic treatment and most continue to have residual psychotic symptoms. Treatment with first- and second-generation antipsychotics may demonstrate similar efficacy; however, patients treated with second-generation antipsychotics may be more likely to adhere to treatment.
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