Michele Hill

The treatment of cognitive impairment in schizophrenia

Cognitive deficits are major contributors to disability in schizophrenia. Many pharmacologic targets have been identified for cognitive enhancing agents, including receptors involved in dopaminergic, glutamatergic, GABAergic, serotonergic and cholinergic neurotransmission. In addition, new approaches to drug development have been directed towards neuroprotection and the facilitation of neuroplasticity. While several pharmacologic agents and cognitive remediation have shown promise in early trials, no treatment has yet demonstrated efficacy in large replication trials. The experience with different pharmacologic targets is reviewed and methodologic issues are discussed with recommendations for future research.

Strategies for Improving Treatment Adherence in Schizophrenia and Schizoaffective Disorder

Nonadherence with medication treatment is common but difficult to detect in patients with schizoaffective disorder and schizophrenia, almost half of whom take less than 70% of prescribed doses. Like patients in all areas of medicine, patients with schizoaffective disorder weigh the perceived benefits of medications against perceived disadvantages, but this process is complicated by their impaired insight, the stigma of the diagnosis, and the often troubling side effects of antipsychotic medication. Interventions to improve adherence include encouraging acceptance of the illness, drawing analogies with treatment for chronic medical disease, and involving the patient in decision making. Clinicians must remain nonjudgmental, encouraging patients to disclose problems with adherence and anticipating that improvement in adherence may require a prolonged effort. Selection of antipsychotic medication is critical to avoid adverse side effects, and some medications may provide a sense of well-being, such as improvement in insomnia, anxiety, or depression. Depot (rather than oral) antipsychotics can improve adherence and provide the clinician with reliable information about the dosage of medication received, which can be used for purposes of dose adjustments or to guide response to relapse.

Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia

IMPORTANCE More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. OBJECTIVES To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. DESIGN Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12. SETTING Three community mental health centers affiliated with academic medical centers in the United States. PARTICIPANTS Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale. INTERVENTION One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo. MAIN OUTCOME MEASURES Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale). RESULTS Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. CONCLUSIONS Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00611806.

Prospective relationship of duration of untreated psychosis to psychopathology and functional outcome over 12 years.

BACKGROUND The duration of untreated psychosis is well recognised as an independent predictor of symptomatic and functional outcome in the short term and has facilitated the development of worldwide early intervention programmes. However, the extent and mechanisms by which it might influence prognosis beyond a decade remain poorly understood. METHODS The authors examined the relationship between duration of untreated psychosis and outcome 12years after a first episode of psychosis and assessed whether its relationship with function is affected by symptoms in a prospective, 12-year follow-up of an epidemiologically-based inception cohort. RESULTS Longer duration of untreated psychosis predicted poorer remission status, more severe positive and negative symptoms, and greater impairment in general functioning, social functioning and quality of life at 12years on standardised measures, independent of other factors at baseline. It was not associated with gainful employment, for which education was the only predictor, or independent living, for which age was the only predictor. The relationship between duration of untreated psychosis and functional outcome was mediated by concurrent psychopathology, particularly negative symptoms. CONCLUSIONS These results provide qualified support for the potential long-term benefit of reduction in the duration of untreated psychosis in terms of improvement in symptoms and functional outcome. Its failure to predict real-life outcomes such as independent living and gainful employment could reflect the importance of pre-existing socio-cultural factors such as individual opportunity. The relationship between duration of untreated psychosis and negative symptoms was largely responsible for its effect on function, suggesting a possible long-term protective mechanism against disability.

Nonadherence to Medication Four Years After a First Episode of Psychosis and Associated Risk Factors

OBJECTIVES This study examined concurrent associations and predictors at first indication of nonadherence to antipsychotic medication four years after a first episode of psychosis. METHODS A prospective cohort of 171 patients in urban Ireland with a first episode of psychosis was followed up four years after inception (follow-up primary analysis, N=84; secondary analysis, N=104). RESULTS At the four-year follow-up 76% were adherent and 24% were not. Nonadherence was concurrently associated with substance misuse (p<.01), increased symptomatology (p<.01), less insight (p=.01), lower global functioning (p<.01), and negative attitudes toward medication (p<.01). Compared with other patients, those who were nonadherent had more readmissions (p=.01). Predictors of future nonadherence were substance misuse (p=.02) and duration of untreated psychosis (p=.04). CONCLUSIONS This prospective investigation confirms previous cross-sectional studies. The association between longer duration of untreated psychosis and nonadherence warrants further research because it could be interpreted as further evidence of the importance of early intervention.

Schizophrenia for Primary Care Providers: How to Contribute to the Care of a Vulnerable Patient Population

Patients with schizophrenia represent a vulnerable population with high medical needs that are often missed or undertreated. Primary care providers have the potential to reduce health disparities experienced by this population and make a substantial difference in the overall health of these patients. This review provides primary care providers with a general understanding of the psychiatric and medical issues specific to patients with schizophrenia and a clinically practical framework for engaging and assessing this vulnerable patient population and assisting them in achieving optimal health. Initial steps in this framework include conducting a focused medical evaluation of psychosis and connecting patients with untreated psychosis to psychiatric care as promptly as possible. Given the significant contribution of cardiovascular disease to morbidity and mortality in schizophrenia, a top priority of primary care for patients with schizophrenia should be cardiovascular disease prevention and treatment through regular risk factor screening, appropriate lifestyle interventions, and other indicated therapies.

Treatment adherence in schizophrenia and schizoaffective disorder.

Medication nonadherence is common and difficult to detect in patients with schizoaffective disorder and schizophrenia. Roughly 50% of patients take less than 70% of prescribed doses. Many factors contribute to nonadherence, including poor illness insight, a negative attitude toward medication, substance abuse, and disorganization. Interventions to improve adherence consist of advising acceptance of illness, drawing analogies with treatment for chronic medical disease, and involving the patient in decision making. Clinicians must remain nonjudgmental, encouraging patients to disclose problems with adherence and anticipating that improvement in adherence may require a prolonged effort. Selection of medication is critical to avoid side effects and to provide a sense of well-being, which can result from improvement in insomnia, anxiety, or depression. Depot antipsychotics can improve adherence and provide the clinician with reliable information about the dosage of medication received for purposes of dose adjustments or to guide response to relapse.

Clozapine: key discussion points for prescribers.

Clozapine is the most effective antipsychotic medication for treatment-refractory schizophrenia and is also approved for suicidality in schizophrenia patients. However, it can cause significant medical morbidity and requires intensive medical monitoring once prescribed. Perhaps due to lack of familiarity with its use, it is underused in clinical practice and its initiation often delayed. This article reviews the literature on clozapine in order to measure its potential effectiveness against its adverse effects and ultimately aims to serve as a useful summary for clinicians in their everyday prescribing.

Prodromal symptoms and remission following first episode psychosis.

INTRODUCTION Describing the trajectory of prodromal symptoms has obvious appeal in supporting advances towards sub-clinical intervention. Identifying clinical phenomena associated with unfavourable illness outcomes could have greater significance in explaining some heterogeneity within and between psychotic disorders and advancing understanding of pre-psychotic typologies. Few studies have assessed the continuity, if any, between prodromal phases and illness outcome one year after treatment. METHODS We assessed 375 people with first-episode psychosis (FEP) and 215 (57.4%) were seen approximately one year later. We performed factor analysis on prodromal symptom items obtained by interview with families and participants and identified a five-factor solution. We determined whether these factors predicted non-remission from psychosis in the presence of other factors that may predict outcome including premorbid adjustment, duration of prodrome and untreated psychosis (DUP), baseline symptoms and DSM-IV diagnoses. We used random forest classification to predict the most important variables and logistic regression to identify specific predictors. RESULTS We identified five prodromal symptom factors comprising Negative Symptoms, General Psychopathology, Reality Distortion, Strange Ideas and Irritability. Prodromal symptoms did not predict a greater risk of non-remission with the exception of Irritability and this factor was also associated with earlier age at onset, being male and a diagnosis of substance-induced psychosis. Being male, DUP and baseline positive symptoms predicted non-remission at one year. CONCLUSION Prodromal symptoms were not linked with outcome after a year of treatment which could be explained by greater heterogeneity in illness psychopathology which may be more pronounced in broad FEP diagnoses at different stages. It could also be explained by prodromal symptoms exerting greater influence earlier in the course illness.

EFFECTS OF FOLIC ACID AND VITAMIN B12 SUPPLEMENTATION ON NEGATIVE SYMPTOMS AND RELATED MRI INDICES

patients treated with stable doses of antipsychotics were randomly assigned to two groups that received an infusion of either sodium nitroprusside or placebo for four hours. Psychiatric symptoms were assessed at baseline and every hour during the infusion with the Brief Psychiatric Rating Scale (BPRS) and the negative subscale of the Positive and Negative Syndromes Scale (PANNS-n). Additional assessments were made 12 hours after the infusion, daily for seven days, and weekly for four weeks. Cognitive tests (Stroop Color Word Test, N-back, and FAS) were administered at baseline and 12 hours after the end of the infusion. No side effects were reported by the participants. All the clinical and demographic characteristics of the sample including age, education, duration of disease, gender, diagnostic subtype, and type of antipsychotic in use were matched across groups. Symptom ratings were significantly reduced in the group treated with sodium nitroprusside, but not in the placebo group. Cognitive performance was also significantly improved in the nitroprusside group compared to placebo. There were no significant differences between the two groups regarding the physiological parameters analyzed (systolic and diastolic blood pressure, cardiac rhythm, and oxygen saturation). The strategy of treating schizophrenia patients for four hours with 0,5 mcg/kg/min sodium nitroprusside improved psychopathology and cognitive function. Our findings support the hypothesis that the NMDA-NO-GMPc pathway is affected in schizophrenia and that nitric oxide donors such as sodium nitroprusside could thus be a promising approach in the management of the disorder. Although exciting, these results are preliminary and must be replicated by future studies.