Change In Negative Symptoms Research Articles

The Impact of Insight on Functioning in Patients With Schizophrenia or Schizoaffective Disorder Receiving Risperidone Long-Acting Injectable

This post hoc analysis explored the role of insight as a mediator of functioning in a 52-week, double-blind, international trial of 323 patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable. Measures included the Positive and Negative Syndrome Scale (PANSS) insight item, PANSS factors, Clinical Global Impressions-Severity (CGI-S), Strauss-Carpenter Levels of Functioning (LOF), Personal and Social Performance (PSP) scale, and a cognitive test battery. Correlation/regression analyses examined associations between demographic and clinical characteristics, including insight, and functional measures. Insight scores correlated significantly with CGI-S, PANSS subscales, PSP, LOF, and several cognitive measures. Regression models demonstrated that changes in insight, changes in negative symptoms, and study duration were significantly associated with PSP and LOF total change scores. Findings identified important variables to consider for intervention to improve functioning in schizophrenia.

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

This study compared patients with schizophrenia whose antipsychotic medications were switched to manage treatment-resistant positive psychotic symptoms with those for whom another antipsychotic was added. Psychiatrists' characteristics and perceptions of effectiveness of the medication change on clinical outcomes were also reported. Psychiatrists participating in a nationally representative mailed survey (N=209) reported on the clinical features, management, and response to the change in antipsychotic medication (added versus switched) of one adult patient with treatment-refractory schizophrenia under their care for at least one year. Thirty-three percent of patients were treated with an added antipsychotic medication. Compared with patients whose antipsychotic medications were switched, those with an added antipsychotic medication were more likely to be female, to have received care from the same psychiatrist for more than two years, and to have been recently prescribed an antidepressant. Compared with psychiatrists who switched antipsychotic prescriptions, those who added an antipsychotic reported that the change was less likely to reduce positive symptoms, improve functioning, and prevent hospitalization. Psychiatrists who added rather than switched antipsychotics reported more frequent attendance at educational programs sponsored by a pharmaceutical company. Consistent with other lines of research and practice guideline recommendations, psychiatrists perceive antipsychotic polypharmacy to be a generally ineffective strategy for treatment-resistant positive psychotic symptoms. In light of these findings, efforts to identify and implement more effective evidence-based pharmacologic approaches should be undertaken.

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

Die Bedeutung der Negativsymptomatik für kognitive Defizite bei Patienten mit Erstmanifestation einer Schizophrenie

Patients with a first episode of schizophrenia may suffer from psychotic and disorganised symptoms, such as delusions, hallucination, bizarre behaviour and formal thought disorder, and from negative symptoms including flattening of affect, alogia, apathy/avolition, anhedonia and deficits in attention. There is solid evidence that neuropsychological abnormalities are also present at this stage of the illness, comprising deficits in domains of attention, executive function, verbal and non-verbal memory, spatial abilities, psychomotor functions, etc. We have recently shown that early, treatment-induced improvement of negative symptoms is significantly associated with cognitive performance during a follow-up period of two years. In this study the impact of early, treatment-induced change of negative symptoms on cognitive performance during a follow-up of 2 years was examined in a larger sample of neuroleptic-naive patients with first-episode schizophrenia. Forty-three patients with a diagnosis of schizophrenia or schizoaffective disorder according to DSM-IV underwent a comprehensive clinical and neuropsychological test battery at the time of study inclusion and after approximately 5 weeks, 6, 12 and 24 months of follow-up. A healthy comparison group with similar age, gender distribution and parental socio-economic status was also included. Patients showed marked cognitive deficits at baseline and throughout the follow-up. Early, treatment-induced improvement of negative symptoms predicted better cognitive performance at follow-up. Early, treatment-induced improvement of cognitive performance was significantly associated with less negative and psychotic symptoms. The results of this study suggest a clinical relevant association between early change in negative symptoms and cognitive outcome, and between early improvement of cognitive performance and symptomatic outcome. Negative symptoms and cognitive deficits should be considered as primary treatment targets in the early course of schizophrenia.

Effect of 5-HT<char aid="99740019" id="sub">1A</char> Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients

Objective: The serotonin 5-HT 1A receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT 1A receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment. Method: Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the –1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months. Results: The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms. Conclusions: These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Effect of 5-HT 1A Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients

The serotonin 5-HT(1A) receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT(1A) receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment. Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the -1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months. The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms. These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Insight and its relationship to clinical outcomes in patients with schizophrenia or schizoaffective disorder receiving long-acting risperidone

Poor insight is common in schizophrenia, predictive of non-compliance, and an impediment to effective patient management. We hypothesized that long-acting risperidone would be associated with enhanced insight, contributing to improved quality of life measures. In an international, open-label 50-week study, stable patients received long-acting risperidone every 2 weeks. Assessments included the Positive and Negative Syndrome Scale [PANSS; item G12 rated 'impaired insight and judgment' from 1 (no impairment) to 7 (severe impairment)]; Clinical Global Impressions-Severity (CGI-S); and the Medical Outcomes Study Short-form 36-item Health Survey (SF-36) (patient-rated quality of life). Correlation and regression post-hoc analyses examined associations between insight and other measures. At baseline, 314 (51.1%; N=614) patients had impaired insight (G12=3-7) and 83 (26.4%) achieved normal or near normal ratings at endpoint (G12=1-2). Symptom severity corresponded with insight: baseline mean+/-SD PANSS total scores were 56.0+/-14.4 in patients without impaired insight (G12=1-2); 73.4+/-15.7 with mild-moderate impairment (G12=3-4); and 86.0+/-17.4 with severe impairment (G12=5-7). These scores improved significantly in each group at endpoint (P<0.001). Improved insight ratings correlated with improvements in CGI-S (r=0.37); PANSS disorganized thought (r=0.46); negative symptoms (r=0.32); and anxiety/depression (r=0.24; P<0.001 all comparisons), but not quality of life ratings. The change in insight did not contribute significantly to the variance in SF-36 scores; however, changes in negative symptoms, anxiety/depression and CGI-S scores did contribute significantly. Long-acting risperidone was associated with improvements in insight, symptom domains, clinical status and quality of life measures. Associations were noted between patient-rated quality of life and specific symptom domains, but not insight.

The effects of the Columbia shuttle disaster on the daily lives of older adults: Findings from the VA Normative Aging Study

During 2002–2003 the VA Normative Aging Study conducted an eight-day diary survey of stressors and well-being. A sub-sample of 19 men and 13 women (mean age = 71.78) completed daily questionnaires before and after the Columbia shuttle exploded on 1st February 2003, presenting a unique look into peoples’ daily lives before and after a tragic event. Results indicated no significant changes in negative affect or physical symptoms, but people reported significant decreases in both positive affect and memory failures on days following the shuttle explosion. Implications of these findings and directions for future research are discussed.

Does negative symptom change relate to neurocognitive change in schizophrenia? Implications for targeted treatments

Negative symptoms and cognitive dysfunction are among the most challenging obstacles in the treatment of schizophrenia. It is unknown to what extent they are overlapping or independent disease processes. In the search for targeted treatments of negative symptoms and cognitive impairments, it is imperative to determine their longitudinal relationship. 267 stable outpatients with schizophrenia in a work and cognitive rehabilitation program were evaluated using symptom measures and a comprehensive neuropsychological test battery at baseline and at the conclusion of rehabilitation, 6 months later. Baseline negative symptom, neuropsychological variables and change scores from intake to follow-up on these variables were correlated. These analyses were repeated with a subsample ( n = 161) who had clinically significant negative symptoms at baseline. ANCOVA's were performed to compare patients whose negative symptoms improved by 5 points or more ( n = 69) with those whose negative symptoms got worse by 5 points or more ( n = 26) on their neurocognitive performance at follow-up. Intake negative symptoms were significantly associated with theory of mind and visuomotor processing. Results failed to support a lawful relationship between change in negative symptoms and neurocognition. These findings suggest that negative symptoms and neurocognition should be viewed as relatively independent targets for intervention.

Double-Blind, Placebo-Controlled Study of Modafinil for Fatigue and Cognition in Schizophrenia Patients Treated With Psychotropic Medications

To assess the effects of modafinil on fatigue, symptoms, attention, working memory, and executive functioning in schizophrenia patients treated with psychotropic medications. Twenty-four patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (10 men and 14 women) were randomly assigned to modafinil up to 200 mg a day (N = 13) or placebo (N = 11) as an adjunct therapy in an 8-week, double-blind, placebo-controlled study. Data were collected from May 18, 2001 to September 11, 2003. Four subjects terminated the study early, including one because of worsening of psychosis during the first week taking modafinil. In the modafinil (N = 10) and placebo (N = 10) groups, fatigue improved significantly over time (p < .01), but there were no differences between groups on changes in fatigue, positive and negative symptoms, or cognition. Fatigue improved in both groups, and there were no differences between groups on changes in fatigue, symptoms, attention, working memory, or executive functioning. Lack of differences between groups may be due to small sample size or possible regression to the mean in the placebo group.

Relation Between Estradiol and Negative Symptoms in Men With Schizophrenia

The authors tested the hypothesis that estradiol would be associated with negative symptoms in 30 male schizophrenia inpatients. Medications were switched from typical to atypical antipsychotics. Estradiol concentrations were inversely correlated with negative symptoms significantly before the switch and at a trend level of significance after the switch. Changes in negative symptoms were positively correlated with those in estradiol concentrations at a trend level of significance. Estradiol could be a biological marker for negative symptoms even in male schizophrenia patients.

Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine. Baseline glycine levels or glycine/serine ratios predicted the Scale for the Assessment of Negative Symptoms - Sum of the Global Scales and Avolition-Apathy after 6 wk of clozapine treatment. These results indicate the association of these amino acid measures with response to clozapine in terms of negative symptoms in patients with schizophrenia.

Effects of Acute Tryptophan Depletion on Negative Symptoms and Smoking Topography in Nicotine-Dependent Schizophrenics and Nonpsychiatric Controls

We studied the effect of acute tryptophan depletion (ATD), which transiently reduces brain serotonin, on negative symptoms and cigarette smoking topography in schizophrenic smokers. Nicotine-dependent schizophrenics (n=11) and nonpsychiatric controls (n=8) were examined after ingesting comparable mixtures that do and do not deplete plasma tryptophan. Tryptophan-depleting and placebo mixtures were administered double-blind and in counterbalanced order. Conditions were separated by a 1-week interval. Psychopathologic symptoms (negative symptoms, depression) and smoking topography (time to first puff, number of puffs per cigarette, puff duration, interpuff interval, cigarette duration, and percentage of cigarette smoked) were measured before ingestion and again beginning 5 h after each mixture, corresponding to the time of maximal tryptophan depletion. Analyses were conducted using repeated measures analyses of variance (psychopathologic symptoms) and analyses of covariance (smoking topography) controlling for cigarette length. We found that ATD influenced smoking topography in both schizophrenics and nonpsychiatric controls in a manner suggestive of increased desire to smoke. Schizophrenics exhibited increased puff duration and decreased cigarette duration. Controls displayed increased puff duration. ATD did not produce changes in negative symptoms or depression. Compromising brain serotonin via ATD appears to intensify smoking behavior in nicotine-dependent individuals directly, rather than indirectly through changes in either mood or psychopathologic symptoms.

Changes in negative symptoms and EEG in schizophrenic patients after repetitive Transcranial Magnetic Stimulation (rTMS): an open-label pilot study

The effects of repetitive transcranial magnetic stimulation (rTMS) on schizophrenic negative symptoms (NS) and EEG topography were investigated in this pilot study. 10 patients with predominant NS were treated with 10 Hz rTMS over the left dorsolateral prefrontal cortex for 5 days. For NS ratings, the Scale for the Assessment of Negative Symptoms (SANS) was used. Both ratings and EEG recordings were obtained pre- and post-rTMS. Electrical activity changes were computed by Low Resolution Brain Electromagnetic Tomography. SANS showed an improvement after rTMS, from 49.0 (SD: 10.7) to 44.7 (SD: 11.8) (means). EEG frequency bands were changed fronto-temporally (right) and were mainly decreases in delta- and beta- and increases in alpha1-activity, as well as decreases in beta-activity in the temporal and parieto-occipital regions (left). Although we are aware of the limitations of this study, we assume a slight improvement in NS. The EEG findings refer to a possible neurophysiologic correlate of their improvement after rTMS.

Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women

The aim of this study was to compare the pharmacodynamic response to a neuroactive steroid, pregnanolone, before and during different hormonal settings of postmenopausal hormone replacement therapy (HRT), using natural progesterone. A second aim was to investigate whether the response to pregnanolone was associated with cyclicity in negative mood symptoms during treatment. Twenty six postmenopausal women with climacteric symptoms were administered HRT in a randomized, double blinded, placebo-controlled, crossover study. The women received 2 mg oral estradiol (E(2)) continuously during two 28-day cycles and 800 mg of vaginal progesterone or placebo sequentially for the last 14 days of each treatment cycle. Pharmacodynamic response to pregnanolone was assessed before treatment, and during the last week of each treatment cycle, by comparing the effects of intravenous pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) on saccadic eye velocity (SEV), saccade acceleration, saccade latency and self-rated sedation. Throughout the study daily symptom rating scales were kept. According to the daily symptom rating scales, patients were divided into two groups; one group who displayed a significant variance in negative mood symptoms during HRT (cyclicity) and one group with no cyclical changes in negative mood symptoms during treatment. During treatment with either E(2) alone or E(2)+progesterone the response in saccadic eye movement parameters and in self-rated sedation to pregnanolone was enhanced compared to pretreatment values. The SEV, saccade acceleration and sedation responses to pregnanolone was also increased in women expressing cyclicity in negative mood symptoms compared to women with no cyclical changes in negative mood during HRT. In conclusion, during treatment with either E(2) alone, or E(2)+progesterone, pregnanolone sensitivity was increased. Women expressing cyclicity in negative mood symptoms were more sensitive to pregnanolone than women without symptom cyclicity during HRT.

Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol.

Previous studies suggest that the risk of tardive dyskinesia is increased with higher doses of conventional antipsychotics. This study evaluates the 12-month incidence of tardive dyskinesia in subjects with first-episode psychosis who were treated with very low doses of haloperidol. Fifty-seven subjects with first-episode psychosis and a DSM-IV diagnosis of schizophreniform disorder, schizophrenia, or schizoaffective disorder were treated according to a fixed protocol with a mean dose of haloperidol of 1.68 mg/day and prospectively studied for 12 months. Subjects were assessed for extrapyramidal symptoms and psychiatric symptoms at 3-month intervals. Data were gathered from 1999 to 2001. Twelve-month incidence of probable or persistent tardive dyskinesia according to Schooler and Kane criteria was 12.3% (N = 7). Subjects with tardive dyskinesia did not differ from the rest of the sample regarding gender, race, duration of untreated psychosis, or baseline clinical characteristics. Subjects with tardive dyskinesia were older compared with subjects without tardive dyskinesia (37.14 +/- 9.23 vs. 27.30 +/- 8.09 years, respectively; t = -2.77, df = 30, p = .01) and received higher mean doses of haloperidol at 12 months (2.80 +/- 1.64 vs. 1.39 +/- 0.69 mg/day, respectively; t = -3.13, df = 25, p = .004). Cox regression analysis revealed that age at inclusion (p = .031), percentage change in negative symptoms (p = .028), and dose of haloperidol at 12 months (p = .016) were significant predictors of risk for tardive dyskinesia. Incidence of tardive dyskinesia was at least as high as in other samples treated with standard doses of conventional antipsychotics. Subjects at risk for tardive dyskinesia could not be identified on the basis of initial clinical features or acute treatment response. Risk of tardive dyskinesia was related to age, antipsychotic dose, and worsening of negative, depressive, and parkinsonian symptoms.

Symptom outcome 1 year after admission to an early psychosis program.

To determine the change in positive, negative, and depressive symptoms after 1 year in an early psychosis program. One hundred and eighty subjects were included from the first 257 admissions for a first episode of psychosis to a comprehensive early psychosis program. Most had a diagnosis of schizophrenia or schizophreniform disorder. Subjects were assessed on admission to the program and at 3, 6, and 12 months after admission. All 180 subjects completed the 1-year assessment. Assessment measures included the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. There was a clinically and statistically significant improvement in positive symptoms by 3 months, depression increased at 3 months but significantly improved by 12 months, and negative symptoms changed little over the first year. The differential changes in symptoms in the first year after admission have implications for treatment.

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment

The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms. Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CYP2D6 genotype determined by polymerase chain reaction analysis for alleles *1 to *15 and *17. The serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes. Treatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.

An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Depression in patients with schizophrenia during an acute psychotic episode.

There is disagreement about whether depressive symptoms in schizophrenia are part of the basic disease process, or whether they represent adverse effects of treatment with antipsychotic medications. In a sample of initially antipsychotic drug-free acutely hospitalized patients with schizophrenia (N = 104), we measured change in depressive symptoms after 4 weeks of treatment. We also examined the relationship of changes in depressive symptoms to changes in positive and negative schizophrenic symptoms. Depressive symptoms improved after 4 weeks of antipsychotic medication treatment, and their improvement corresponded with improvement in both positive and negative schizophrenic symptoms. These results suggest that depressive symptoms in schizophrenia are related to the disease process itself, at least during acute exacerbations of schizophrenia. Depressive symptoms may be responsive to antipsychotic medications directly or as a secondary response to improvement in positive and negative symptoms.