Typical Neuroleptic Medication Research Articles

Antipsychotics

Antipsychotics

Reduced implicit and explicit sequence learning in first-episode schizophrenia

A high prevalence of deficits in explicit learning has been reported for schizophrenic patients, but it is less clear whether these patients are impaired in implicit learning. Deficits in implicit learning indicative of a fronto-striatal dysfunction have been reported using a serial reaction-time task (SRT), but the impact of typical neuroleptic medication and chronicity remains controversial. The present study compared 37 patients with first-episode schizophrenia treated with atypical neuroleptics and 37 healthy matched control participants on two sequence learning tasks: a modified SRT for implicit sequence learning and a serial generation task (SGT) for explicit sequence learning. The two tasks were designed to be procedurally equivalent, in order to provide better comparability between implicit and explicit performance. Although unaffected in global cognitive functioning, schizophrenic patients were significantly impaired in implicit and explicit sequence learning. Deficient sequence learning in schizophrenic patients was neither related to psychopathology nor to chlorpromazine equivalent daily dosage. As performance was impaired even though patients were exclusively treated with atypical neuroleptics, the present findings concur with converging evidence of a sequence learning deficit inherent in schizophrenia. This deficit would be consistent with a fronto-striatal dysfunction and might constitute a crucial factor for the acquisition of new information.

Neuroleptic malignant syndrome associated with ziprasidone in an adolescent

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal disorder characterized by fever, muscular rigidity, delirium, and autonomic instability. Although the classic presentation of NMS has been most commonly associated with the typical neuroleptic medications, sporadic cases in association with atypical neuroleptic medications have been reported.Objective: We describe a case report of a pediatric patient with NMS associated with the use of the atypical antipsychotic medication ziprasidone hydrochloride.Methods: After a MEDLINE search of relevant literature (key terms: atypical antipsychotic, ziprasidone, neuroleptic malignant syndrome, and NMS; years: 1995–2004), no reports of NMS in association with ziprasidone in the pediatric population were identified.Results: The patient was a 15-year-old male adolescent with a history of schizoaffective disorder treated with ziprasidone capsules, 80 mg QD for 8 weeks prior to presentation. He was brought to the emergency department because the family noted that the child had a tactile fever; was rigid, diaphoretic, tremulous, and difficult to arouse; and had persistent urinary incontinence. The patient was admitted to the pediatric intensive care unit, where he remained rigid and unresponsive except for incoherent speech. He was treated for a presumptive diagnosis of NMS with IV dantrolene sodium (2 mg/kg q6h) to reduce the sequele of NMS; urinary alkalinization with sodium bicarbonate to maintain a urinary pH of 6.5 to 7.0; cardiac, pulse oximetry, and vital sign monitoring; and supportive care, including IV saline hydration.Conclusion: We present this case to alert physicians of the possibility of NMS in adolescent patients treated with ziprasidone.

Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study.

To determine whether acute neuroleptic-induced parkinsonism and akathisia were risk factors for the later development of tardive dyskinesia (TD) in patients on typical neuroleptics. Of 100 subjects examined for parkinsonism and akathisia after the initiation of typical neuroleptic medication, 78 were followed up for TD after a mean 41.2 months. Nine (11.5%) subjects were diagnosed with TD, predominantly manifesting as oro-facial dyskinesia. They had greater severity of parkinsonism and akathisia at baseline, and a larger neuroleptic load, than those who did not develop TD. On regression analyses, parkinsonism at baseline was a significant predictor of later TD. Examined independently of parkinsonism, akathisia severity at 2 weeks was also a significant predictor of later TD. Acute drug-induced parkinsonism and akathisia are both predictors of TD, with parkinsonism having greater predictive value. Acute and tardive extrapyramidal syndromes may share vulnerability factors.

Psychiatrie im Wandel: neuronale Netzwerkstörungen lassen sich mit moderner Kernspintomographie sichtbar machen

Over the last 20 years major advances in mathematics and computing opened up remarkable opportunities for studying the function, biochemistry and microstructure of the human brain. Magnetic resonance imaging (MRI) in neuroscience describes the functional organisation of the brain at the level of large neuronal groupings, networks and systems. By relating these to normal and disturbed information processing and behaviour in humans, means for the systematic analysis of the spatio-temporal functional architecture of the human brain along with the plasticity of that architecture are provided. At the same time, the focus of psychiatric research is increasingly moving from the differential description of phenomenology and disease course to an understanding of the biological basis of mental disorders. This also becomes evident when considering the spectrum of schizophrenia where investigators have consistently tried to identify the neurobiological substrate of information-processing deficits that seem characteristic for schizophrenic patients. Widespread abnormalities in different stages of information processing seem to lead to a cascade of downstream effects on higher cortical functions such as working memory or concept formation. In recent studies, the phenotypic characterisation of basic information processes as well as cognitive abnormalities in schizophrenic patients have been elaborated with new MRI methods. In both neuroleptic naive first episode and chronically ill schizophrenic patients in remission functional MRI demonstrated a dysfunction of the first relay station of the thalamus and in the prefrontal cortex as compared to normal controls. Furthermore, this technique revealed significant differences in prefrontal function between patients with typical and atypical antipsychotics. Using MR-spectroscopy in accordance with these functional data patients receiving typical neuroleptic medication showed a significantly lower mean NAA (marker for neuronal viability) in the anterior cingulate gyrus in comparison to the group of patients receiving atypical antipsychotic drugs, and had significantly more perseveration errors in the WCST. No significant group differences were found in either the creatine and phosphocreatine signal or the signal from choline-containing compounds. However, there was a clear association between the age-corrected NAA signal in the cingulate gyrus and the perseveration errors as well as the length of atypical treatment. In addition to differences between patients and healthy subjects these findings also showed differences within the patient group depending on treatment. These results support the hypothesis of a dysfunction in prefronto-temporo-limbic and early visual information-processing networks in schizophrenia. Furthermore, there was a specific relationship between neuronal and neuropsychological functioning. In keeping with animal data these results also indicate that chronic treatment with antipsychotics has regionally specific effects on the prefrontal cortex. Based on functional and metabolic MRI, circuit dysfunctions have been demonstrated within prefrontal and thalamic areas. In future, the non-invasive monitoring of therapeutic interventions with modern imaging methods in a multimodal approach may help to improve treatment by allowing approaches to be tailored for the individual patient.

Sex differences in verbal memory in schizophrenia patients treated with “typical” neuroleptics

The relationship between sex and verbal learning and memory was investigated in 70 males and 36 females with a diagnosis of schizophrenia. Ninety-seven percent of the sample was receiving typical neuroleptic medication as treatment and had never received atypical medications. Selected scores from the California Verbal Learning Test (CVLT) [Delis, D.C., Kramer, J.H., Kaplin, E., Ober, B., 1987. The California Verbal Learning Test—Research Edition. Psychological Corporation, New York] were dependent variables in a series of hierarchical multiple regression analyses. Predictors comprised demographic, clinical and general cognitive measures. Sex was the most powerful predictor of both cumulative learning (Trial A5 recall) and the absolute number of words recalled after 20 min (Long-Delay Free Recall), accounting for 14% and 16% of score variance, respectively. Chlorpromazine-equivalent dose was negatively related to learning and recall. However, recall savings (Percent Retention) was unrelated to any predictor. This pattern of results parallels sex differences observed in the general population, albeit at a lower overall level of performance and with the suggestion of greater relative deficit in males. Schizophrenia does not eliminate and may even increase the advantage women demonstrate over men in some aspects of verbal memory.

Low Heart Rate Variability Is Not Caused by Typical Neuroleptics in Schizophrenia Patients

Both elevated cardiovascular mortality and low cardio-vagal (parasympathetic) heart rate variability (HRV)--a risk factor for postmyocardial infarction--are reported in schizophrenia (SZ). Since a number of medications have strong effects of cardiac conductivity, we thought it important to examine if typical neuroleptic medications might also affect HRV. We examined cardiac vagal activity during both neuroleptic treatment and a drug-free condition in seven SZ patients who were participating in a pilot double-blind, crossover study of placebo and haloperidol treatment. Twenty-four-hour Holter electrocardiograms were analyzed for high frequency HRV, quantitated as the percent of successive normal interbeat intervals greater than 50 milliseconds (PNN50), which is a good index of parasympathetic cardiac modulation. The patients showed unchanged PNN50 (8.4+/-9.5 versus 8.3+/-10.5; t=.22, df=6, P=.5) between the haloperidol treatment and drug-free conditions. Despite the elapsed time, change in medication, and altered clinical state, the PNN50s were highly correlated (Spearman r=.98, P=.000). SAPS positive symptom scores declined with treatment from 12.8+/-6.5 to 8.5+/-3.5; paired t=3.26: df=6; P=.01. PNN50s were significantly associated with positive (r=-.86, df=6, P=.012) and negative symptom scores (r=-.87, df=6, P=.01). We found low cardiovagal modulation in medication-free SZ patients that was associated with core SZ symptoms and was unchanged by haloperidol and benztropine treatment. The reduced HRV in SZ patients at baseline may render them at greater cardiovascular risk than healthy subjects when treated with medications having strong cardiovascular effects.

Favorable effect on neuronal viability in the anterior cingulate gyrus due to long-term treatment with atypical antipsychotics: an MRSI study.

In the present study, we evaluated 23 chronic schizophrenic patients under stable clinical conditions to determine the association between neuronal viability, as measured by in vivo(1)H magnetic resonance spectroscopic imaging (MRSI), and antipsychotic drug effects in the anterior cingulate cortex. Careful screening of the medication history showed that 11 of these patients had been treated with traditional neuroleptics only, while the others had switched to atypical antipsychotics due to non-response to traditional drugs. The group of patients receiving typical neuroleptic medication showed a mean NAA that was lower than in the group of patients receiving atypical antipsychotic drugs. Removing the duration of illness effect indicated a significant correlation between the NAA signal in the anterior cingulate gyrus and time on atypical drugs in patients under long-term atypical antipsychotic treatment. In contrast, patients with traditional medication revealed progressive decrease in the NAA level. These results suggest a favorable effect on neuronal viability in the anterior cingulate gyrus due to long-term treatment with atypical antipsychotics.

Abnormal Eeg Patterns in Treatment-Resistant Schizophrenic Patients

This study was conducted in order to compare the EEG patterns of schizophrenics who do not respond to typical neuroleptics with those who do respond under typical neuroleptic medication and a group of controls. Absolute (AP) and relative power (RP), and inter- and intrahemispheric correlations were calculated. Nonresistant schizophrenics showed lower delta RP, higher alpha 1 AP and RP and higher correlation between prefrontal areas than the resistant ones and controls. Resistant schizophrenics showed lower alpha2 RP, lower betal and beta2 in temporal but higher beta2 AP and RP in occipital derivations, and higher intrahemispheric correlation between Fp2 and F4 and lower between F8 and T4 than the nonresistant and controls. The resistants also showed a higher antero-posterior betal and beta2 index than the controls. We concluded that the EEG pattern showed by the nonresistants may be associated with their good neuroleptic response that was not present in the resistant schizophrenics.

An audit of psychiatric case notes in relation to antipsychotic medication and information giving.

This paper reports upon a Welsh Office funded "clinical effectiveness" project. The project aimed to produce evidence-based practice guidelines for depot neuroleptic medication. An audit was conducted to establish current practice regarding the provision of illness and treatment specific information to out-patients and their informal carers. Sixty-five patients' case-notes, under the care of a single community mental health team were examined for evidence of the type, nature and frequency of information given to patients receiving typical depot neuroleptic medications. Service guidelines were produced and are presented.

Increased incidence of dyskinesias and other behavioral effects of re-exposure to neuroleptic treatment in social colonies of Cebus apella monkeys.

Typical neuroleptic medications are still administered to as many as 40% of patients receiving antipsychotic treatment in the US. Intermittent administration or interruption of long-term neuroleptic medication for schizophrenia may increase the incidence of human tardive dyskinesias, and similarly may produce increasingly marked motor side-effects, parkinsonism, and other behavioral pathologies in non-human primates. Given these similarities, we addressed the issue of prolonged and intermittent typical neuroleptic treatment and dopaminergic function during a 5-year, multi-phase study with social colonies of Cebus apella monkeys. In the previously reported phase 1, we examined the effects of 48 weeks of exposure to, followed by withdrawal from, fluphenazine decanoate (FPZ). Phase 3 reported here examined the effects of 18 weeks of re-exposure to FPZ in these same monkeys, 91 weeks after discontinuation of their phase 1 FPZ treatment. Analysis of blood plasma FPZ indicated levels of 0.22+/-0.08 ng/ml for the six injections during the re-exposure period (n=54), comparable to the 0.24+/-0.07 ng/ml levels measured during our original treatment with this dose. Acute dyskinesias and dystonias increased by 300% upon re-exposure to FPZ; 15 of 18 FPZ-treated animals exhibited oral-buccal dyskinesias and all exhibited torticollis or retrocollis. Retreatment with FPZ was also associated with highly significant reductions in Self- and Environment-Directed Behavior and Directed Affiliation, effects similar to those seen during the original phase 1 FPZ treatment. Although FPZ re-treatment was associated with a significant reduction in Directed Aggression (an effect that was more robust than that observed during phase 1), in phase 3, we again observed an increase in Directed Aggression during early drug discontinuation when animals were in a stress-inducing situation. These results both support our phase 1 conclusion that typical neuroleptic medications may contribute to negative symptoms of schizophrenia and provide additional evidence for the possibility of increased aggression in stressful situations when medication is discontinued. Additionally, the results indicate that intermittent treatment with typical neuroleptics may dramatically increase the incidence of dystonias and dyskinesias.

The Kraepelinian Dichotomy: Evidence From Developmental and Neuroimaging Studies

The Kraepelinian Dichotomy: Evidence From Developmental and Neuroimaging Studies

142. Longitudinal study of basal ganglia volume in schizophrenic patients

Studies from our center as well as others have found that neuroleptics influence basal ganglia volume. Typical neuroleptics are cited as leading to an increase in basal ganglia volume, while the opposite is said to occur following medication with atypical neuroleptics (risperidone, clozapine and olanzapine) and have delt with patients receiving mostly atypical neuroleptics. However most of the basal ganglia volume studies thus far have relied on relatively small sample sizes. Our aim in completing this study is to follow up on earlier work (measuring basal ganglia volume and medication exposure in a small sample male schizophrenia spectrum patients), assessing for the effects of typical and atypical neuroleptic medication on basal ganglia volume of both male and female patients. We will present the findings of our ANN (artificial neural network) derived volume measurements of the caudate and putamen in over 40 schizophrenia spectrum patients who had baseline and two year follow-up MR scans (and whose exposure to both typical and atypical neuroleptic medication had been quantified during this time).

Effects of age, medication, and illness duration on the N-acetyl aspartate signal of the anterior cingulate region in schizophrenia

The authors performed a MRSI study of the anterior cingulate gyrus in 19 schizophrenic patients under stable medication and 16 controls in order to corroborate previous findings of reduced NAA in the anterior cingulate region in schizophrenia. Furthermore, correlations between NAA in the anterior cingulate gyrus and age or illness duration have been determined. A decreased NAA signal was found in the anterior cingulate gyrus of patients compared to controls. Subdividing the patient group into two groups depending on medication revealed that the group of patients receiving a typical neuroleptic medication showed a lower mean NAA in comparison to the group of patients receiving atypical antipsychotic drugs. No significant group differences in the creatine and phosphocreatine signal or the signal from choline-containing compounds were found. The NAA signal significantly correlated with age, and therefore, individual NAA values were corrected for the age effect found in the control group. The age-corrected NAA signal in schizophrenia correlated significantly with the duration of illness. The detected correlations of NAA decrease with age and illness duration are consistent with recent imaging studies where progressing cortical atrophy in schizophrenia was found. Further studies will be needed to corroborate a possible favorable effect of atypical antipsychotics on the NAA signal.

Interactive risk factors for treatment adherence in a chronic psychotic disorders population

This study identified the unique and primary contributions of several concurrent risk factors for poor adherence to treatment recommendations in a clinic population of individuals with chronic psychotic disorders, i.e. 48% had DSM-IV diagnoses of schizoaffective disorder, 38% had schizophrenia, paranoid type, 12% had schizophrenia, undifferentiated type, and 2% had affective disorder with psychotic features. The target cohort consisted of 87 consecutive admissions to a continuing day treatment program. As part of a services-oriented quality assurance program, clinical staff completed rating scales for all patients. These included the BASIS-32 rating scale, which consisted of the following five subscales: psychosis; depression/anxiety; impulsive/addictive behavior; relation to self and others; and daily living and role functioning, and the Working Alliance Inventory-short form (therapist version), which consisted of the following three subscales: goal; task; and bond. These data were used to identify risk factors that weaken a patient’s adherence to medication and non-medication treatment during the first 2 weeks of treatment in the clinic. Medication treatment consisted of both typical and atypical neuroleptic medications, with most patients being on multiple medications. Correlational analyses suggested that many of the risk factor variables were significantly associated with poor treatment adherence. Regression analyses suggested that the degree of psychoticism was most strongly associated with poor adherence to medication treatment and that difficulties relating to self and others were the strongest predictor of poor adherence to non-medication treatment. A large-sample services research design such as this can begin to determine patterns of associations between previous identified risk factors and poor treatment adherence in individuals with chronic psychotic disorders.

Clozapine versus typical neuroleptic medication for schizophrenia.

Long-term drug treatment of schizophrenia with conventional antipsychotics has limitations: 25-33% of patients have illnesses that are treatment-resistant. Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment. To evaluate the effects of clozapine for schizophrenia in comparison to typical antipsychotic drugs. Publications in all languages were searched from the following databases: Biological Abstracts (1982-1999), The Cochrane Library CENTRAL (Issue 2, 1999), Cochrane Schizophrenia Group's Specialised Register (1999), EMbase (1980-1999), ISI Citation Index, LILACS (1982-1999), MEDLINE (1966-1999), and PsycLIT (1974-1999). Reference list screening of included papers was performed. Authors of recent trials and the manufacturer of clozapine contacted. All randomised controlled trials comparing clozapine with typical antipsychotic drugs were included by independent assessment by at least two reviewers. Data were extracted independently by at least two reviewers. Authors of trials published since 1980 were contacted for additional and missing data. Odds ratios (OR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated with the Peto method. A random effects model was used for heterogeneous dichotomous data. Where possible the numbers needed to treat (NNT) or needed to harm (NNH) were also calculated. Weighted or standardised means were calculated for continuous data. Currently the review includes 31 studies, 26 of which are less than 13 weeks in duration. These studies include 2589 participants, most of whom were men (74%). The average age was 38 years. There was no difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at end of the study. Clinical improvement was seen more frequently in those taking clozapine (random effects OR 0.4 CI 0.2-0.6, NNT 6) both in the short and the long term. Also, in the short term, participants on clozapine had fewer relapses than those on typical antipsychotic drugs (OR 0.6 CI 0.4-0.8, NNT 20 CI 17-38), and this may be true for long-term treatment as well. Symptom assessment scales showed a greater reduction of symptoms in clozapine-treated patients. Clozapine treatment was more acceptable than low-potency antipsychotics such as chlorpromazine (OR 0.6 CI 0.4-0.9) but did not differ from acceptability of high-potency neuroleptics such as haloperidol (random effects OR 0.8 CI 0.4-1.5). Clozapine was more acceptable in long-term treatment than conventional antipsychotic drugs (random effects OR 0.4 CI 0.2-0.7, NNT 6 CI 3-111). Patients were more satisfied with clozapine treatment (OR 0.5 CI 0.3-0.8, NNT 12 CI 7-37), but they experienced more hypersalivation, temperature increase, and drowsiness than those given conventional neuroleptics. However, clozapine patients experience fewer motor side effects and less dry mouth. The clinical efficacy of clozapine was more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (random effects OR 0.2 CI 0.1-0.5, NNT 5 CI 4-7) and symptom reduction. Thirty-two percent of treatment resistant people had a clinical improvement with clozapine treatment. This systematic review confirms that clozapine is convincingly more effective than typical antipsychotic drugs in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse. Patients were more satisfied with clozapine treatment than with typical neuroleptic treatment. (ABSTRACT TRUNCATED

Normalization of information processing deficits in schizophrenia with clozapine.

The authors tested the hypothesis that the use of an atypical drug, clozapine, for patients with schizophrenia is related to less impairment in information processing deficits (assessed by prepulse inhibition of the startle response) than is the use of typical antipsychotics. Two groups of schizophrenic patients--receiving either clozapine or a range of typical antipsychotics--were tested for prepulse inhibition (a reduction in response to a starting stimulus, if preceded briefly by a weak, nonstartling stimulus; measured at prepulse-to-pulse intervals of 30 msec, 60 msec, and 120 msec) of the acoustic startle response and compared with a group of healthy volunteers. Patients receiving typical antipsychotics showed less prepulse inhibition with 30-msec and 60-msec prepulse trials than did comparison subjects. Clozapine-treated patients showed normal levels of prepulse inhibition. Clozapine is superior to typical antipsychotics in normalizing prepulse inhibition, presumably because of its pharmacological effects on prefrontal regions of the brain or its effects on a broader range of neuroreceptors.

Biogenic amines as predictors of response to clozapine treatment in early-onset schizophrenia

The purpose of the present study was to assess the relationship between plasma monoamine levels and changes in psychopathology in a sample of children and adolescents with schizophrenia (DSM-III-R criteria) during conventional neuroleptic therapy and during short-term treatment with clozapine. After failing on conventional neuroleptics in open-labeled clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11–20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders ( n = 7) and non-responders ( n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2–90.3 pg/ml; non-responders ranging from 92.5–473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of methoxyhydroxyphenylglycol (MHPG) and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic.

Blood biogenic amines during clozapine treatment of early-onset schizophrenia

The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14-22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 +/- 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and nonresponders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.

Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: Effects of typical neuroleptics on the brief psychiatric rating scale

There has been little investigation of the effect of neuroleptic medication on the structure of symptoms in schizophrenia. In this study, 135 male schizophrenic patients were rated with the Brief Psychiatric Rating Scale (BPRS) after 4 weeks of treatment with typical neuroleptic medication and after 2 weeks free of neuroleptics, with the order of assessment varying across patients. Confirmatory factor analyses (CFA) found that there were no differences in symptom structure across medication status and no differences in the structure of symptoms in treatment responders and nonresponders. The typical 5-factor BPRS model fit the data poorly and the fit improved considerably through deletion of items measuring symptoms not associated with schizophrenia, suggesting that some of the symptoms that contribute to a total BPRS score may be adding primarily error variance. Although the sample size in this study is limited, the results suggest that using total BPRS scores to measure severity of schizophrenic symptoms should be reconsidered.