Negative Symptoms In Chronic Schizophrenia Research Articles

A Review on Biological Mechanisms of Negative Symptoms in Chronic Schizophrenia

Research about the negative symptoms of chronic schizophrenia (SZ) is still lagging behind, in order to more comprehensively and systematically understand the biological and molecular mechanisms behind them, as well as to explore more valuable research directions and treatment options. By summarizing the results of previous studies and exploring them at the levels of neurobiology, genetics, molecular biology and microbiology, the authors provide a preliminary review of the new research progress in recent years. The authors hypothesize neurodevelopmental disorders by thoroughly investigating the anatomical features of various brain regions and the corresponding abnormalities in neurotransmitters. This paper then provides a relatively fresh perspective by summarizing the potential pathogenic mechanisms in terms of the brain-gut axis and metabolic syndrome. Ultimately, it is determined that the pathophysiology of chronic schizophrenia is associated with multiple biological mechanisms within the body, primarily arising from neurological abnormalities within the brain. On the basis of this, the author provides a conceptualization of the pathophysiology and a potential course of treatment.

Retraction: Abdallah MS, Mosalam EM, Hassan A, etal. Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial. CNS Neurosci. Ther. 2023;29:354-364 (https://doi.org/10.1111/cns.14010).

Retraction: Abdallah MS, Mosalam EM, Hassan A, etal. Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial. CNS Neurosci. Ther. 2023;29:354-364 (https://doi.org/10.1111/cns.14010) The above article, published online on November 07, 2022 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the journal's Editor-in-Chief, Xiaoming Hu, and John Wiley and Sons Ltd. Following publication, the Editor-in-Chief raised concerns about the integrity of the clinical trial. An investigation revealed significant issues regarding the reliability of the reported data. As a result, the Editor-in-Chief no longer has confidence in the validity of the results presented in this article.

Retraction: Abdallah MS, Mosalam EM, Hassan A, etal. Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial. CNS Neurosci. Ther. 2023;29:354-364 (https://doi.org/10.1111/cns.14010).

Retraction: Abdallah MS, Ramadan AN, Omara-Reda H, etal. Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder. CNS Neurosci. Ther. 2021;27:1540-1548 (https://doi.org/10.1111/cns.13731) The above article, published online on September 21, 2021 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the journal's Editor-in-Chief, Xiaoming Hu, and John Wiley and Sons Ltd. Following publication, multiple concerns were raised by a third party about the integrity of the clinical trial. An investigation revealed significant issues regarding the reliability of the reported data. As a result, the Editor-in-Chief no longer has confidence in the validity of the results presented in this article.

High-definition transcranial direct current stimulation for treating cognitive and negative symptoms in chronic schizophrenia – A sham-controlled proof of concept study

Objectives: Cognitive and negative symptoms are core symptoms of schizophrenia affecting interpersonal and socio-occupational functioning. Impaired dorsolateral prefrontal cortex (DLPFC) function is implicated in negative and cognitive symptoms. Conventional transcranial direct current stimulation (tDCS) to DLPFC has attracted interest as an add-on treatment for these symptoms. High-definition tDCS (HD-tDCS), an optimized form of tDCS, has the potential for more focalized neuromodulation. Studies suggest that an increased number of sessions may increase the effectiveness of stimulation. Hence, we aimed to evaluate the efficacy of 20 sessions of HD-tDCS over the left DLPFC in the improvement of cognitive and negative symptoms in chronic schizophrenia (>2 years continuous illness). Material and Methods: Twenty patients with chronic schizophrenia with predominantly cognitive and negative symptoms were enrolled in this sham-controlled trial. Participants received 20 sessions of HD-tDCS at 2 mA for 20 min, that is, twice daily over 10 days. Montreal cognitive assessment and scale for assessment of negative symptoms were used to assess outcome variables. Assessments were carried out at baseline, 2 weeks, and 6 weeks, respectively. Results: Significant improvement was noted in both active and sham groups across all outcome variables over time. However, a statistically significant decrease in negative symptoms in the active group was noted, which was maintained at the end of 6 weeks, but there was no statistically significant improvement in cognitive symptoms between the active and sham groups at 6 weeks. The stimulation protocol was well tolerated. Conclusion: HD-tDCS has substantial potential in the treatment of negative symptoms; however, its role in cognitive symptoms needs further evaluation.

Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs

QuestionThis umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.Study selection and analysisFollowing the Preferred Reporting Items for Systematic Reviews...

The efficacy of homestyle rehabilitation on negative symptoms in chronic schizophrenia: A randomized controlled trial.

Schizophrenia is a debilitating mental disorder with a high disability rate that is characterized by negative symptoms such as apathy, hyperactivity, and anhedonia that can make daily life challenging and impair social functioning. In this study, we aim to investigate the effectiveness of homestyle rehabilitation in mitigating these negative symptoms and associated factors. A randomized controlled trial was conducted to compare the efficacy of hospital rehabilitation and homestyle rehabilitation for negative symptoms in 100 individuals diagnosed with schizophrenia. The participants were divided randomly into two groups, each persisting for 3 months. The primary outcome measures were the Scale for Assessment of Negative Symptoms (SANS) and Global Assessment of Functioning (GAF). The secondary outcome measures included the Positive Symptom Assessment Scale (SAPS), Calgary Schizophrenia Depression Scale (CDSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). The trial aimed to compare the effectiveness of the two rehabilitation methods. Homestyle rehabilitation for negative symptoms was found to be more effective than hospital rehabilitation, according to the changes in SANS (T = 2.07, p = 0.04). Further analysis using multiple regression indicated that improvements in depressive symptoms (T = 6.88, p < 0.001) and involuntary motor symptoms (T = 2.75, p = 0.007) were associated with a reduction in negative symptoms. Homestyle rehabilitation may have greater potential than hospital rehabilitation in improving negative symptoms, making it an effective rehabilitation model. Further research is necessary to investigate factors such as depressive symptoms and involuntary motor symptoms, which may be associated with the improvement of negative symptoms. Additionally, more attention should be given to addressing secondary negative symptoms in rehabilitation interventions.

Repeated transcranial magnetic stimulation for treating the negative symptoms of schizophrenia

Objective To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on the negative symptoms of chronic schizophrenia and on the P300 component of schizophrenics′ event-related potentials (ERPs). Methods Ninety convalescing schizophrenia patients were randomly divided into a 5 Hz group, a 10 Hz group and a 15 Hz group, each of 30. The three groups were treated with the corresponding 5 Hz, 10 Hz or 15 Hz rTMS once a day, five times a week for five consecutive weeks. The P300 ERPs of all three groups were tested before and after the treatment. Any curative effect was evaluated using the scale for the assessment of negative symptoms (SANS). Results After the treatment, the average SANS score of the 10 Hz group was significantly different from that before the treatment and also from those of the other two groups after the treatment. After the treatment, significant improvement was also observed in the amplitude of P300 in the 10 Hz group. The treatment′s effectiveness was negatively correlated with age and longer course of the disease. Conclusion rTMS at 10 Hz is the most effective of the protocols tested for improving the negative symptoms of schizophrenia and improving cognitive functioning. Key words: Schizophrenia; Transcranial magnetic stimulation; Event-related potentials

T52. N-ACETYL-CYSTEINE ADD-ON TREATMENT LEADS TO AN IMPROVEMENT OF FORNIX WHITE MATTER INTEGRITY IN EARLY PSYCHOSIS

BackgroundBeneficial effects of N-acetyl-cysteine (NAC) on negative symptoms in chronic schizophrenia have been reported in two studies. A recent study in early psychosis from our group, did not report significant improvement in negative symptoms (potentially linked to the modest baseline levels) but showed improvement in cognition (i.e. processing speed) and an increase in the brain antioxidant glutathione (GSH) levels, indicating good target engagement.1 Indeed, research in animal models highlights the critical role of redox regulation by brain GSH for white matter maturation and maintenance. Given the strong evidence of white matter (WM) alterations in schizophrenia as well as the current lack of etiological treatments, redox dysregulation is an interesting target. The current study aims at investigating the impact of NAC, a precursor of GSH, the main antioxidant in the brain, on WM integrity in patients in the early psychosis phase. We focused on the fornix bundle that has been shown to be impaired in an animal model of oxidative stress2 (i.e. impaired GSH synthesis) as well as in early psychosis patients.3MethodsWM diffusion properties were estimated using generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI) brain scans acquired in patients who received either NAC (n=10; mean age=25.3 ± 5.7; males/females 9/1) or placebo (n=10; mean age=24.8 ± 7.9; males/females 5/5) as add-on treatment over 6-months. GSH levels were measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (MRS).ResultsA non-parametric longitudinal voxel-based analysis limited to the fornix revealed a time x treatment interaction which reached significance in the body of the fornix (corrected p<.04) with NAC patients showing an increase in gFA over 6-month of treatment. Importantly, improvement of gFA (i.e. increase) in the fornix of early psychosis patients (NAC and placebo) correlated with increase in cerebral GSH levels (r=.67; p<.005).DiscussionThis study is the first to assess the effect of NAC on WM integrity as assessed by diffusion weighted-imaging in the early phase of psychosis. WM alterations appear early in the illness and become widespread in a more chronic phase of the disease.4 To the best of our knowledge there is currently no approved medication for schizophrenia that show significant effect on WM integrity. In this study, effects of NAC on WM integrity in the fornix were significant despite the limited sample size. This is a small-scale proof of concept study, which was very demanding for early psychosis patients and needs replication in a larger study. Its potential properties to counteract WM deficits may be even more important in individuals at clinical high risk for psychosis. As NAC add-on treatment is safe with no side effects, this study paves the way for preventive approach at the early stages of psychosis.

Cilostazol adjunctive therapy in treatment of negative symptoms in chronic schizophrenia: Randomized, double-blind, placebo-controlled study.

To evaluate the efficacy and safety of cilostazol, a selective inhibitor of phosphodiesterase III, as an adjunctive to risperidone in alleviating the negative symptoms of schizophrenia. Eighty-four in-patients with diagnosis of chronic schizophrenia participated in a randomized, placebo-controlled trial and underwent 8weeks of treatment with either cilostazol (50mg twice a day) or placebo as an adjuvant to risperidone. Participants were assessed using the positive and negative syndrome scale (PANSS) at baseline and at weeks 2, 4, 6, and 8. The primary outcome measure of the trial was to evaluate the efficacy of cilostazol compared to placebo in improving the PANSS negative subscale score. General linear model repeated measures demonstrated significant effect for time×treatment interaction on negative subscale scores (p<.001) and PANSS total (p=.006) but did not demonstrate significant effect on the PANSS positive (p=.37) and general (p=.06) subscales. Frequency of adverse events was not significantly different between the 2 treatment groups. No serious adverse event was observed. An 8-week course of treatment with cilostazol as an adjunct to risperidone showed a favorable safety and efficacy profile in patients with schizophrenia.

Antipsychotic Augmentation with Venlafaxine for Treatment of Negative Symptoms in Chronic Schizophrenia - A Case Series

Negative symptoms represent a core feature in schizophrenia and the deficit syndrome in chronic schizophrenic patients is closely related to their poor outcome and global failure in community adaptation. Atypical antipsychotics have been widely used in the treatment of negative symptoms in schizophrenia, and tend to produce a better response when used in association with antidepressants. We describe a case series of patients with a clinical diagnosis of residual type of schizophrenia, who have undergone an augmentative treatment of antipsychotic medication with venlafaxine. Both primary and secondary negative symptoms, as well as the overall functioning in these patients were substantially improved following this treatment. This is the first clinical study describing the combination of venlafaxine with both conventional antipsychotics and novel antipsychotics, such as risperidone, to treat successfully both secondary and primary negative symptoms in schizophrenia. We also discuss possible modes of action of the joint use of this particular antidepressant with antipsychotic medication.

Efficacy and safety of extract of Ginkgo biloba as an adjunct therapy in chronic schizophrenia: A systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis

Our study was to review and evaluate the efficacy and safety of extract of Gb (EGb) as an adjuvant therapy to antipsychotics in chronic schizophrenia treatment. We searched Pubmed/Medline, Embase, PsycINFO, the Cochrane library, and especially the Chinese periodical databases. Finally, eight randomized, double-blind, placebo-controlled trials (RCTs) of 1033 patients were enrolled, with 571 cases in EGb group and 462 in placebo. The result showed that EGb had a significant difference in ameliorating total and negative symptoms of chronic schizophrenia as an adjuvant therapy to antipsychotics. Thus, the EGb therapy plus antipsychotics might be more efficacious. Although the studies describing adverse reactions showed no distinguishable difference between EGb and placebo group in mean total scores of Treatment Emergent Symptom Scale (TESS) or a Rating Scale for Extrapyramidal Side Effects (RSESE), the results of subscores varied in different studies. In addition, the severity of side effects of EGb might be related to its daily dosage. Therefore, the safety of EGb therapy in chronic schizophrenia treatment might need more evidence. And all of these eight trials were carried out in China; thus, the results might be restricted to the race and we need more high-quality studies of multi-center and randomized double-blind clinical trials to compare, analyze, and confirm the findings further.

1382 – High prevalence of low testosterone levels in male patients with schizophrenia

Introduction Recent neuroendocrinological studies have suggested that gonadal sex hormones play a significant role in the pathophysiology of schizophrenia. Low testosterone levels are also associated with negative symptoms in chronic schizophrenia. Patients receiving treatment for schizophrenia or schizoaffective disorder also show high rates of sexual dysfunction. Studies suggest that testosterone augmentation may play a potential therapeutic role in these patients. Objectives To study a cohort of schizophrenia patients for the presence of hypotestosteronemia. Aims To establish that low testosterone hormone levels occur at a lower age in schizophrenia population. Methods We reviewed the total testosterone levels of all male schizophrenic patients seen in our office over a period of one year for a routine yearly physical. The blood was tested by LabCorp using the liquid chromatography/tandem mass spectrometry (L/MS-MS). Normal values using this sensitive method are between 348.0–1197 ng/dL. Results There were a total of 61 male schizophrenia patients who had their testosterone levels tested during this period. Their ages ranged from 22 to 48 years. 23 (38%) out of the 61 men had serum testosterone less than 348 ng/dl, while 38 (62%) had testosterone levels between 348 ng/dl and 1197 ng/dl. None had testosterone levels above normal. Conclusions A significant number of our male patients with schizophrenia had hypotestosteronemia. Since gonadal sex hormones play a significant role in the patho-physiology of schizophrenia, testosterone levels should be routinely measured in the male patients. The role of testosterone supplementation in these patients needs to be further explored.

Psychometric analysis in support of shortening the Scale for the Assessment of Negative Symptoms

Despite recent emphasis on the measurement and treatment of negative symptoms, studies of the Scale for the Assessment of Negative Symptoms (SANS) identify different symptom clusters, offer mixed support for its psychometric properties and suggest that it is shortened. The current study objective is to examine the psychometric properties of the SANS and the feasibility of a short research version of the SANS. Data were re-analyzed from three clinical trials that compared placebo and amisulpride to 60 days. Participants had chronic schizophrenia and predominantly negative symptoms (n=487). Baseline data were examined with exploratory factor analysis and Item Response Theory (IRT) to identify a short SANS. The short and original SANS were compared: with confirmatory factor analysis at endpoint; and on symptom response with mixed modeling to compare. Results showed that at baseline the SANS consisted of three factors labeled Affective-flattening, Asociality and Alogia-inattentiveness. IRT suggested a short SANS with 11 items and 3 response options. Comparisons of the original and short SANS showed: the short version was a better fit to the data based on confirmatory factor analysis at endpoint; similar significant (p<.001) correlations between the baseline and subsequent scores; similar reliability; and similar significance (p<.05) on response based on mixed modeling. It is concluded that a short SANS is feasible to assess predominantly negative symptoms in chronic schizophrenia in research settings.

Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis

Treatment of negative symptoms in chronic schizophrenia continues to be a major clinical issue. To analyse the efficacy of add-on antidepressants for the treatment of negative symptoms of chronic schizophrenia. Systematic review and meta-analysis of randomised controlled trials comparing the effect of antidepressants and placebo on the negative symptoms of chronic schizophrenia, measured through standardised rating scales. Outcome was measured as standardised mean difference between end-of-trial and baseline scores of negative symptoms. There were 23 trials from 22 publications (n = 819). The antidepressants involved were selective serotonin reuptake inhibitors, mirtazapine, reboxetine, mianserin, trazodone and ritanserin; trials on other antidepressants were not available. The overall standardised mean difference was moderate (-0.48) in favour of antidepressants and subgroup analysis revealed significant responses for fluoxetine, trazodone and ritanserin. Antidepressants along with antipsychotics are more effective in treating the negative symptoms of schizophrenia than antipsychotics alone.

Antipsychotic Augmentation with Venlafaxine for Treatment of Negative Symptoms in Chronic Schizophrenia - A Case Series

Negative symptoms represent a core feature in schizophrenia and the deficit syndrome in chronic schizophrenic patients is closely related to their poor outcome and global failure in community adaptation. Atypical antipsychotics have been widely used in the treatment of negative symptoms in schizophrenia, and tend to produce a better response when used in association with antidepressants. We describe a case series of patients with a clinical diagnosis of residual type of schizophrenia, who have undergone an augmentative treatment of antipsychotic medication with venlafaxine. Both primary and secondary negative symptoms, as well as the overall functioning in these patients were substantially improved following this treatment. This is the first clinical study describing the combination of venlafaxine with both conventional antipsychotics and novel antipsychotics, such as risperidone, to treat successfully both secondary and primary negative symptoms in schizophrenia. We also discuss possible modes of action of the joint use of this particular antidepressant with antipsychotic medication.

Analysis of association between the catechol- O-methyltransferase ( COMT) gene and negative symptoms in chronic schizophrenia

Negative symptoms commonly seen in chronic schizophrenia are related to prefrontal hypodopaminergia. Dysfunction of the catechol- O-methyltransferase ( COMT) gene has long been thought to confer susceptibility to schizophrenia because of its catalytic activity for dopamine degradation. The present study is an attempt to perform a quantitative trait test for genetic association between the COMT gene and negative symptoms in a Chinese population. A total of 290 unrelated individuals with schizophrenia patients were recruited and their symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED programme to examine the correlation between the scored negative symptoms and the coding single nucleotide polymorphisms (SNPs) present in the COMT gene. The rs4633-rs4680 haplotype showed significant association with the overall score of negative symptoms, and four individual negative symptoms, including blunted affect, emotional withdrawal, poor rapport and passive/apathetic social withdrawal. SNP rs4680 (Val/Met) showed significant association with blunted affect. The present finding suggests that the COMT gene may a etiologically contribute to the severity of negative symptoms in schizophrenia, but its precise mechanism needs further investigating.

Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia

This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were: criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo. They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms, and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post-trial scores and its pooled standard deviation were used to compute standardized mean difference (SMD). Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=-0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored.

A 12-week, double-blind, placebo-controlled trial of donepezil adjunctive treatment to risperidone in chronic and stable schizophrenia

There is considerable incentive to develop new treatment strategies that effectively target cognitive deficits in schizophrenia. One of the theoretically promising novel treatment candidates is acetylcholinesterase inhibitors that increase the synaptic levels of cholinergic, nicotinic, and muscarinic receptor activity. The purpose of this study was to assess the efficacy of donepezil as an adjuvant agent in the treatment of chronic schizophrenia in particular for cognitive impairments. This investigation was a 12-week, double-blind study of parallel groups of patients with stable chronic schizophrenia. Thirty patients were recruited from inpatient and outpatient departments, age ranging from 22 to 44 years. All participants met DSM-IV-TR. diagnostic criteria for schizophrenia. To be eligible, patients were required to have been treated with a stable dose of risperidone as their primary antipsychotic treatment for a minimum period of 8 weeks. The subjects were randomized to receive donepezil (10 mg/day) or placebo, in addition to risperidone (4–6 mg/day). Clinical psychopathology was assessed with Positive and Negative Syndrome Scale (PANSS). Cognition was measured by a cognitive battery. Patients were assessed by a psychiatrist at baseline and after 8, and 12 weeks after the medication started. The PANSS scores and cognitive performance were used as the outcome measures. The donepezil group had significantly greater improvement in the negative symptoms over the 12-week trial. There were no differences between the donepezil and placebo groups on any neurocognitive assessments at endpoint (week 12). The present study indicates donepezil as a potential adjunctive treatment strategy for negative symptoms of chronic schizophrenia.

Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: a double-blind placebo-controlled study

Despite the availability of atypical antipsychotics, the treatment of negative symptoms in schizophrenia remains a challenge. This study was designed to confirm the positive effect observed in our pilot study with paroxetine as augmentation to antipsychotics in the treatment of negative symptoms in chronic schizophrenia. Twenty-nine patients with chronic schizophrenia, as defined by DSM-IV, who scored at least 20 points on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) were randomized for treatment with 30 mg paroxetine or placebo in a double-blind, placebo-controlled study for 12 weeks. Ratings included the PANSS, the Hamilton Rating Scale for Depression (HAM-D) and scales for extrapyramidal side-effects. An intention-to-treat analysis was based on the 25 patients who were available for at least one follow-up assessment. The last observation carried forward principle was applied. The mean score of the negative subscale of the PANSS decreased in both groups. Using an analysis of covariance, there was a significant treatment effect with paroxetine compared to placebo with respect to negative symptoms (-4.53; 95% confidence interval -9.054 to -0.015). The mean HAM-D scores remained almost constant. The study suggests the efficacy of paroxetine with respect to the treatment of negative symptoms in chronic schizophrenia.

Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: A double-blind placebo-controlled study

Despite the availability of atypical antipsychotics, the treatment of negative symptoms in schizophrenia remains a challenge. This study was designed to confirm the positive effect observed in our pilot study with paroxetine as augmentation to antipsychotics in the treatment of negative symptoms in chronic schizophrenia. Twenty-nine patients with chronic schizophrenia, as defined by DSM-IV, who scored at least 20 points on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) were randomized for treatment with 30 mg paroxetine or placebo in a double-blind, placebo-controlled study for 12 weeks. Ratings included the PANSS, the Hamilton Rating Scale for Depression (HAM-D) and scales for extrapyramidal side-effects. An intention-to-treat analysis was based on the 25 patients who were available for at least one follow-up assessment. The last observation carried forward principle was applied. The mean score of the negative subscale of the PANSS decreased in both groups. Using an analysis of covariance, there was a significant treatment effect with paroxetine compared to placebo with respect to negative symptoms (-4.53; 95% confidence interval -9.054 to -0.015). The mean HAM-D scores remained almost constant. The study suggests the efficacy of paroxetine with respect to the treatment of negative symptoms in chronic schizophrenia.