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Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Substance use disorders have a profound impact on the course of severe mental illnesses and on the family, but little research has evaluated the impact of family intervention for this population. To address this question, a randomized controlled trial was conducted comparing a brief (2-3 mo) Family Education (ED) program with a longer-term (9-18 mo) program that combined education with teaching communication and problem-solving skills, Family Intervention for Dual Disorders (FIDD). A total of 108 clients (77% schizophrenia-spectrum) and a key relative were randomized to either ED or FIDD and assessed at baseline and every 6 months for 3 years. Rates of retention of families in both programs were moderate. Intent-to-treat analyses indicated that clients in both programs improved in psychiatric, substance abuse, and functional outcomes, as did key relatives in knowledge of co-occurring disorders, burden, and mental health functioning. Clients in FIDD had significantly less severe overall psychiatric symptoms and psychotic symptoms and tended to improve more in functioning. Relatives in FIDD improved more in mental health functioning and knowledge of co-occurring disorders. There were no consistent differences between the programs in substance abuse severity or family burden. The findings support the utility of family intervention for co-occurring disorders, and the added benefits of communication and problem-solving training, but also suggest the need to modify these programs to retain more families in treatment in order to provide them with the information and skills they need to overcome the effects of these disorders.

Objective: The Helping Older People Experience Success (HOPES) program was developed to improve psychosocial functioning and reduce long-term medical burden in older people with severe mental illness (SMI) living in the community. HOPES includes 1 year of intensive skills training and health management, followed by a 1-year maintenance phase., Method: To evaluate effects of HOPES on social skills and psychosocial functioning, we conducted a randomized controlled trial with 183 older adults with SMI (58% schizophrenia spectrum) age 50 and older at 3 sites who were assigned to HOPES or treatment as usual with blinded follow-up assessments at baseline and 1- and 2-year follow-up., Results: Retention in the HOPES program was high (80%). Intent-to-treat analyses showed significant improvements for older adults assigned to HOPES compared to treatment as usual in performance measures of social skill, psychosocial and community functioning, negative symptoms, and self-efficacy, with effect sizes in the moderate (.37-.63) range. Exploratory analyses indicated that men improved more than women in the HOPES program, whereas benefit from the program was not related to psychiatric diagnosis, age, or baseline levels of cognitive functioning, psychosocial functioning, or social skill., Conclusions: The results support the feasibility of engaging older adults with SMI in the HOPES program, an intensive psychiatric rehabilitation intervention that incorporates skills training and medical case management, and improves psychosocial functioning in this population. Further research is needed to better understand gender differences in benefit from the HOPES program.

Background: Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-D-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients., Materials and Methods: Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug., Results: Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo., Conclusion: Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia.

Background: Daily dosing with d-cycloserine has inconsistently improved negative symptoms in schizophrenia patients, whereas intermittent dosing significantly facilitated exposure-based therapy in two studies of patients with phobic anxiety. In animal models, single-dose administration enhances memory consolidation, but tachyphylaxis develops with repeated dosing. The objective of this exploratory study was to assess whether once-weekly dosing with d-cycloserine will produce persistent improvements in negative symptoms and cognition., Methods: Fifty stable adult schizophrenia outpatients treated with any antipsychotic except clozapine were enrolled and 38 were randomized, double-blind, in a parallel-group, eight-week add-on trial of d-cycloserine 50 mg or placebo administered once-weekly. Symptom rating scales and a cognitive battery were administered at baseline and week 8 before the dose of study drug. As an exploratory analysis of memory consolidation, the Logical Memory Test, modified to measure recall after 7 days, was administered at baseline and after the first weekly dose of d-cycloserine. The primary outcome measures were change from baseline to week 8 on the SANS total score and on a composite cognitive score., Results: Thirty-three subjects (87%) completed the trial. d-cycloserine significantly improved SANS total scores compared to placebo at week 8. Cognitive performance did not improve with d-cycloserine at 8 weeks. Delayed thematic recall on the Logical Memory Test was significantly improved with the first dose of d-cycloserine compared to placebo. Performance on immediate thematic recall and item recall on the Logical Memory Test did not differ between treatments., Conclusions: Once-weekly dosing with d-cycloserine for 8 weeks produced persistent improvement of negative symptoms compared to placebo, although statistical significance was, in part, the result of worsening of negative symptoms with placebo. Consistent with animal models, a single dose of d-cycloserine facilitated memory consolidation tested after 7 days on a test of thematic recall. These results must be considered preliminary since a number of outcomes were examined without correction for multiple tests. These findings suggest that once-weekly dosing with d-cycloserine for the treatment of negative symptoms merits further study, as do d-cycloserine effects on memory consolidation.

The purpose of the present study was to assess posttraumatic stress disorder (PTSD), cognitive function, and quality of life in patients with schizophrenia who had a self-reported history of trauma exposure. Outpatients diagnosed with schizophrenia or schizoaffective disorder were referred to the study. Each patient was assessed with the Positive and Negative Syndrome Scale (PANSS), the Harvard Trauma Questionnaire (HTQ), a cognitive assessment battery, Heinrich's Quality of Life Scale (QLS), and the Behavior and Symptom Identification Scale (BASIS). Eighty-seven subjects who reported experiencing at least one traumatic event were included in the study. Fifteen of 87 (17%) met the DSM-IV criteria for PTSD. The PTSD group had significantly worse overall cognitive performance than the non-PTSD group, especially in the domains of attention, working memory and executive function. In addition, the PTSD group showed significantly worse self-rated quality of life as measured by the BASIS total score. The development of PTSD is associated with poor cognitive function and subjectively, but not objectively, rated low quality of life in patients with schizophrenia. Evaluating PTSD in patients with schizophrenia could have important implications from both clinical and research perspectives.

Objective: The present study was to characterize relationships among sexual functioning, schizophrenia symptoms and quality of life measures. In addition, sexual functioning was compared among patients treated with different antipsychotic agents., Methods: Outpatient subjects were assessed using the Positive and Negative Symptom Scale (PANSS), the Changes in Sexual Functioning Questionnaire (CSFQ) and the Hamilton Rating Scale for Depression (HAMD). Quality of life was assessed using two different instruments: observer-rated Heinrich's Quality of Life Scale (QLS) and self-rated The Behavior and Symptom Identification Scale (BASIS)., Results: One hundred twenty-four patients with schizophrenia or schizoaffective disorder were enrolled in the study. Eight-six patients (69%) completed at least part of the CSFQ assessment, which generated at least one valid subscale score. High rates of sexual impairment were found in both male and female patients (65%-94% across different subscales). For males, higher scores on the PANSS-positive subscale were associated with a lower frequency of sexual activity (p=0.04). For females, higher scores on the PANSS-positive subscale and PANSS-general psychopathology subscale were significantly associated with more difficulty in both sexual arousal and orgasm (p's<0.05). For both males and females, there were no significant relationships between any CSFQ subscale measures and the quality of life measures (p's>0.05). No significant differences were found among three antipsychotic treatment groups (clozapine, olanzapine or typical agents) on any CSFQ subscale measures or quality of life measures after controlling for PANSS total scores (p's>0.05)., Conclusions: Effective treatment strategies still need to be developed to address sexual dysfunction and quality of life in patients with schizophrenia.

Background: The increasing prevalence of overweight and obesity has become a priority public health issue in the United States. Forty to 62% of people with schizophrenia are obese or overweight (1, 2). High morbidity and mortality in schizophrenia may be attributed to an unhealthy lifestyle such as poor diet, lack of exercise, smoking, and substance abuse (3). Obesity is associated with greater risk of developing hypertension, type 2 diabetes, coronary heart disease, stroke, death, and reduced quality of life compared with that found in the general population (4, 5). We performed a cross-sectional study evaluating the dietary intake of patients with schizophrenia or schizoaffective disorder treated with atypical antipsychotic agents., Methods: Dietary intake of 88 patients from an urban community mental health clinic was measured using a four-day dietary record. Nutritional variables included total energy intake, fat, protein, carbohydrate, cholesterol, fiber, sucrose, folate, calcium, sodium, zinc, alcohol and caffeine. Data were compared to the general population using data matched for age, gender, and ethnicity from the National Health and Nutrition Examination Survey (NHANES), 1999-2000., Results: The Body Mass Index (BMI) of the schizophrenia group (M = 31.3, SD = 12.67) was significantly greater than the NHANES group (M = 28.3, SD = 6.62) (p = .001). The schizophrenia group consumed significantly fewer calories, carbohydrate, protein, total fat, saturated fat, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), fiber, folate, sodium and alcohol and significantly more caffeine than the NHANES group., Conclusions: The findings may suggest that obesity in schizophrenia patients is not solely related to food consumption, but perhaps other effects including medication side effects and reduced physical activity. Education and interventions for the schizophrenia population should focus more on overall lifestyle factors such as physical activity and healthy food choices.

Introduction: Delusions may arise from abnormalities in emotional perception. In this study, we tested the hypothesis that delusional schizophrenia patients are more likely than non-delusional schizophrenia patients and healthy participants to assign affective meanings to neutral stimuli., Methods: Unpleasant, pleasant, and neutral words were randomly presented to three subject groups--patients with schizophrenia with prominent delusions, patients with schizophrenia without delusions, and healthy participants. Participants performed three tasks: one in which they decided whether a letter string was a word or a non-word (lexical decision) and two affective classification tasks in which they judged whether words were 1) neutral or unpleasant, or 2) neutral or pleasant., Results: While there were no significant between-group differences in lexical decision performance, patients with delusions showed selective performance deficits in both affective classification tasks. First, delusional patients were significantly more likely than non-delusional patients and healthy participants to classify words as unpleasant. Second, delusional patients took significantly longer than both other groups to correctly classify neutral words in both affective classification tasks., Conclusions: Taken together, these findings suggest that delusions are associated with the explicit misattribution of salience to neutral stimuli.

This study examined clinical predictors of client and therapist alliance ratings early in therapy, the relationship between client and therapist alliance ratings, and the psychometric properties of the Working Alliance Inventory in individuals with schizophrenia receiving manual-based treatment. Assessment of clinical symptoms and social functioning were conducted at baseline, and alliance ratings were obtained at 5 weeks. The Working Alliance Inventory had high internal consistency, but there were low correlations between client and therapist ratings. Results also indicated that social functioning and the activation and autistic preoccupation factors on the Positive and Negative Syndrome Scale were significant predictors of therapists' alliance ratings. There were no significant relationships between clinical predictors and clients' therapeutic alliance ratings. The findings indicate that client interpersonal factors are significant predictors of the therapist-rated alliance in the treatment of schizophrenia. Low correlations between clients' and therapists' ratings of the alliance should be examined in future research.

Objective: The objective of this study was to examine the effects of tobacco abstinence and bupropion treatment on cognitive functioning in adult smokers with schizophrenia in the setting of a randomized, double-blind, placebo-controlled clinical trial of bupropion for smoking cessation., Method: Fifty-three adults with schizophrenia (DSM-IV) took part in a trial of bupropion for smoking cessation. Subjects were enrolled in the study from August 1999 to March 2003. Forty-five subjects remained in the trial at week 4; 41 subjects, 19 taking bupropion and 22 taking placebo, completed the baseline and week 4 cognitive assessments and were included in the analysis of adjusted effects of abstinence and bupropion treatment on cognitive function., Results: Controlling for bupropion treatment and baseline performance, 7 days of tobacco abstinence was associated with slowed motor speed (finger tapping) but was not associated with worsening of performance on tests of attention (AX Continuous Performance Test [AX-CPT]), verbal learning and memory (California Verbal Learning Test [CVLT]), working memory (digit span), or executive function/inhibition (Stroop) and was not associated with worsening of any clinical measures. Controlling for abstinence status, bupropion was associated with reduction (improvement) in reaction time variability on the AX-CPT and with reduction in perseverative errors on the CVLT., Conclusion: We conclude that 1 week of tobacco abstinence is associated with slowed motor speed but is not associated with detectable worsening in performance on a range of neuropsychological tests or clinical symptoms in the subset of patients who were able to quit smoking. We also conclude that bupropion treatment may be associated with improvement in variability of attention.

Background: Attitude toward medications is important for medication adherence. A patient's drug attitude probably reflects a weighing of benefits against experienced or anticipated side effects or risks associated with the medication. We predicted (1) that drug attitudes would be more positive among schizophrenia patients taking second-generation compared to first-generation antipsychotics because of their greater tolerability and efficacy; and (2) that greater insight into illness, fewer extrapyramidal symptoms, and better social functioning would be associated with better attitudes toward psychiatric medication., Method: In a cross-sectional study of 81 DSM-IV-diagnosed schizophrenia outpatients, we used multivariate analysis to determine clinical and demographic predictors of drug attitude. Drug attitude was assessed with the 10-item Drug Attitude Inventory (DAI). The relationship between the DAI and psychopathology, insight, extrapyramidal symptoms, level of functioning, and type of antipsychotic (first-generation versus second-generation versus clozapine) was examined., Results: Less awareness of current symptoms, presence of deficit symptoms, and employment predicted a negative attitude toward psychiatric medications. Extrapyramidal symptoms did not predict drug attitude. Drug attitudes were no different between patients taking first- or second-generation antipsychotics or clozapine., Conclusion: Patients may not favor second-generation over first-generation antipsychotics, and extrapyramidal symptoms may not be a primary factor determining attitudes. While attitudes may be more positive in patients who recognize therapeutic drug effects, patients who work may view medications particularly negatively, possibly due to a sense of stigma. Because drug attitudes may reflect compliance and are difficult to predict, clinicians should inquire directly.