Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice.

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management.

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.

Impaired insight into illness is unrelated to subjective happiness, success, and life satisfaction in schizophrenia.

BACKGROUND: Impaired insight into illness is a common feature of schizophrenia. Improved insight is associated with better treatment adherence and clinical outcomes. At the same time, improving insight has been suggested to increase depressive symptoms and diminish quality of life. The aim of this study was to examine the associations between impaired insight and degree of subjective happiness, perceived level of success, and life satisfaction in patients with schizophrenia spectrum disorders. METHODS: A total of 108 participants with schizophrenia or schizoaffective disorder were included. Data for this study were obtained from our group's previous investigation that examined the relationship between impaired insight and visuospatial attention. Insight into illness was measured by the VAGUS scale, which assesses general illness awareness, accurate symptom attribution, awareness of the need for treatment, and awareness of the negative consequences attributable to the illness. RESULTS: Our results revealed no association among the VAGUS average and subscale scores and degree of subjective happiness, perceived level of success, and life satisfaction. CONCLUSIONS: Our study suggests that insight into illness is not related to subjective happiness, life satisfaction, or perceived level of success in patients with schizophrenia, which is in contrast to previous reports that demonstrate an association between insight into illness and depression.

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) will affect about one in three patients with schizophrenia. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. Despite its effectiveness, concern over side effects, monitoring requirements, and inexperience with prescribing often result in long delays that can expose patients to unnecessary risks and compromise their chances of achieving favorable long-term outcomes. We critically reviewed the literature on clozapine use in TRS, focusing on guidelines, systematic reviews, and algorithms to identify strategies for improving clozapine safety and tolerability. Based on this, we have provided an overview of strategies to support early initiation of clozapine in patients with TRS based on the latest evidence and our clinical experience, and have summarized the key elements in a practical, evidence-based checklist for identifying and managing patients with TRS, with the aim of increasing confidence in prescribing and monitoring clozapine therapy.

Real-World Utilization Patterns of Long-Acting Injectable Antipsychotics in Canada: A Retrospective Study.

Objective: The objective of this study was to analyze the real-world prevalence of long-acting injectable (LAI) antipsychotic use and determine when LAIs are being used in sequencing of antipsychotic medications among Canadian patients with schizophrenia. Methods: This was a retrospective, longitudinal cohort study using Canadian pharmacy prescription data between August 2005 and June 2017. Patients with inferred schizophrenia spectrum disorder were indexed on the date of their first antipsychotic prescription and analyzed for minimum 12 months to track lines of antipsychotic therapy and LAI utilization. Results: A total of 16,300 patients were identified for analysis. 48.2% and 46.0% of index antipsychotic prescriptions were prescribed by a general practitioner/family medicine doctor and psychiatrist, respectively. 1,062 (6.5%) patients used an LAI during the study period. Of those patients, 789 used an LAI within two years of index (74.3% of LAI users; 4.8% of all patients). The majority of LAI use (62.0%) occurred in the third line of therapy or later. 65.0% of patients had tried at least two therapy lines, and most patients reported gaps of six months to one year between treatment lines. Conclusion: Despite their potential to reduce relapse in schizophrenia by improving treatment adherence, this study shows LAIs continue to be under-utilized in Canada. When used, LAIs are positioned late in sequencing of antipsychotic medications, often not initiated until years after diagnosis. Continued preference for oral APs with poor adherence may be negatively impacting prognosis and exacerbating burden of schizophrenia. Efforts should be invested to understand barriers to LAI uptake and advocate for earlier, widespread use of LAIs.

Antipsychotic nonadherence measured by electronic adherence monitoring in stabilized chronic schizophrenia: Clinical implications.

BACKGROUND: There have been a number of studies investigating antipsychotic adherence measured by electronic adherence monitoring (EAM) in patients with schizophrenia. However, no study has looked at overall adherence and both baseline and endpoint illness/symptom severity. METHODS: We performed a secondary analysis of our previous study to examine antipsychotic adherence, as measured by EAM, and illness/symptom severity at baseline and endpoint in patients with schizophrenia. Adherence rates were defined as the proportion of adherent days over 3 months. Adherent days were defined as the subject having taken the medication at the prescribed time, with 2 tolerance margins operationally defined i.e., ±3 h and ±12 h. In addition, a dichotomous version of adherence was defined i.e., if he/she was adherent greater than 80% of the days. Illness severity and symptom severity were assessed using the Brief Psychiatric Rating Scale (BPRS) total score and the Clinical Global Impression - Severity of illness (CGI-S) scale score, respectively. RESULTS: A total of 111 patients were enrolled in the study. Neither continuous or dichotomous adherence rates were significantly associated with baseline or endpoint illness/symptom severity (all Ps ≥ 0.05). The results remained unchanged when adjusting for clinico-demographic characteristics. CONCLUSION: Antipsychotic adherence, as measured by EAM, was not associated with illness/symptom severity at baseline and endpoint in patients with chronic schizophrenia, whose clinical status and adherence pattern were stabilized. This suggests that individuals may be able to achieve clinical stability in the face of maintenance antipsychotic treatment despite variations in adherence.

Schizophrenia: Antipsychotics and drug development.

The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from 'typical' to 'atypical'. Atypicality is reviewed in reference to its original definition, clozapine's role, and developments that now leave the concept's utility in question. In a similar fashion, drug development is reviewed in the context of the illness' multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness' heterogeneity and complexity. Just as 'atypical' as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat 'schizophrenia'.

Cognitive discrepancies, motivation and subjective well-being in people with schizophrenia.

Research indicates that people with schizophrenia often achieve similar levels of subjective well-being (SWB) compared to healthy controls despite prominent symptomatology and significant functional difficulties. Furthermore, compared to healthy controls, young-adult people with schizophrenia differ in the relative importance they place on values, or guiding life principles, associated with educational and occupational success (openness to change), suggesting that changing motivations may contribute to SWB and the apparent motivational deficits commonly reported in this population. The current study sought to better understand these relationships in middle-aged people with schizophrenia or schizoaffective disorder (n=29) versus a relatively healthy group of community controls (n=23). Participants completed measures of SWB and values. They also completed a cognitive battery and interviews concerned with mental and physical health. Patients reported similar levels of SWB compared to controls in the context of significant cognitive, social and vocational difficulties. Moreover, living consistently with values (valued living) predicted SWB in both groups. Lastly, internalized mental illness stigma was negatively associated with openness to change in the patient group. While encouraging from an emotional resiliency perspective, SWB and valued living in people with schizophrenia may hinder motivation towards treatment goals that could otherwise improve functional outcomes in this population.

Exploring the relationship between impaired illness awareness and visuospatial inattention in patients with schizophrenia.

Anosognosia, described as impairment in an individual's ability to perceive and understand their illness, and visuospatial inattention commonly co-occur as a result of structural brain lesions in the right posterior parietal area. Anosognosia or impaired illness awareness is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. A recent pilot study suggests patients with impaired illness awareness have a rightward visuospatial bias. We aimed to examine this relationship in a large sample of patients. This study consisted of 106 patients with schizophrenia spectrum disorder (henceforth, schizophrenia) and 20 healthy controls. Visuospatial attention was assessed using the line bisection test (LBT). Illness awareness was assessed using the VAGUS self-report version. A Welch's t-test was used to examine differences in LBT scores between patients with schizophrenia and healthy controls. Correlation analyses between LBT and VAGUS scores were performed in patients with schizophrenia. For exploratory purposes, intra-subject reliability of the LBT was also examined using a two-way mixed intra-class correlation coefficient (ICC). There were no differences in LBT scores between patients with schizophrenia and healthy controls. In patients, there were no associations between LBT and VAGUS scores. ICCs between two consecutively acquired LBTs were 0.92 (95% CI: 0.81-0.96) in patients with schizophrenia and 0.93 (95% CI: 0.81-0.97) in healthy controls. Our results, using a reliable measure, did not support our previous preliminary finding that suggested a relationship between impaired illness awareness and visuospatial bias in patients with schizophrenia. Future studies should consider more sensitive visuospatial attention tasks when testing this hypothesis.

The Neurobiology of Treatment-Resistant Schizophrenia: Paths to Antipsychotic Resistance and A Roadmap for Future Research.

(Reprinted with permission from NPJ Schizophrenia (2020) 6:1).

Correction to: The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey.

[This corrects the article DOI: 10.1186/s12991-020-00292-5.].

The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey.

BACKGROUND: It is well established that the different antipsychotics used for schizophrenia symptoms differ substantially in their side effects. However, relatively little is known about the impact of these side effects on functioning from the patient's perspective. We aimed to understand how key side effects of second-generation antipsychotics impact the functioning and quality of life (QoL) of patients with schizophrenia. METHODS: This is a cross-sectional, web-based survey of patient-reported side effect burden of antipsychotic drugs in adults with schizophrenia. The survey was deployed in the United States, Canada, Australia, Spain, Italy, Norway, and Denmark. It included sociodemographic and clinical questions, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), and the Glasgow Antipsychotic Side-Effect Scale (GASS). Eight pre-defined key side effects classified as activating ("Shaky hands or arms," "Restlessness," and "Difficulty sleeping"), sedating ("Sleepy during the day", "Feeling drugged or like a zombie," and "Feeling dizzy/Fainted") or other side effects ("Problems enjoying sex" and "Gaining weight"), and additional questions related to impacts on function and quality of life were asked. RESULTS: In total, 435 participants (mean age: 38 years, 53.8% female) were included. The total Q-LES-Q-SF score indicated overall medium satisfaction with their quality of life (score of 44.3; possible range 14-70). The most prevalent side effects were "Sleepy during the day" (83.2%), "Difficulty sleeping" (74.7%), "Dry mouth" (63.9%), "Problems enjoying sex" (53.4%) and "Gaining weight" (52.4%). Women reported the side effects of "Sleepy during the day", "Problems enjoying sex" and "Gaining weight" more frequently than men. Key side effects impacted physical, social, occupational and psychological aspects of functioning. Patients with key side effects often felt frustrated by their experiences. Total Q-LES-Q-SF score showed a significant inverse correlation with the score of pre-defined groups of side effects indicating worse QoL in association with more severe key side effects in these patients. CONCLUSION: Stable patients with schizophrenia taking second-generation antipsychotics live with many side effects, including activating and sedating side effects, sexual side effects, and weight gain. Presence of these side effects is associated with substantial impacts across all aspects of daily functioning and lower quality of life and satisfaction.

Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis.

Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose-response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.

You say "schizophrenia" and I say "psychosis": Just tell me when I can come off this medication.

Individuals experiencing a first episode of psychosis are likely to respond well to treatment with antipsychotic medications. Of those treated for a first episode of schizophrenia, three out of four can expect to achieve remission. The question of how long antipsychotic medication should be continued has been a topic of heated debate in the field. Longitudinal studies of individuals diagnosed with a first episode of psychosis have reported that as many as 30% may be able to come off of medications without relapsing while treatment discontinuation studies have found that very few patients remain in remission off of medication. This paper reviews the literature on relapse rates following a first episode of schizophrenia and identifies factors that contribute to the discrepancies in the rates reported. These factors include sampling considerations, the distribution of psychiatric diagnoses, the duration of follow-up, the rate of medication discontinuation and the criteria used to define illness recurrence. We propose that individuals for whom the diagnosis of their first psychotic episode is determined with ongoing follow-up to be due to schizophrenia are at extremely high risk of relapse and should be advised to continue antipsychotic medication for the long-term. Those whose first episode of psychosis is determined to be due to other causes are also at high risk of illness recurrence off medications. Recommendations for maintenance treatment should be tailored to reflect the risk of relapse and sequelae of relapse associated with specific causes of first episode psychosis.