Adherence to clozapine vs. other antipsychotics in schizophrenia.

BACKGROUND: To date, there have been no studies evaluating adherence to clozapine with electronic adherence monitoring (EAM) such as the Medication Event Monitoring System (MEMS® ). METHODS: In outpatients with schizophrenia, we conducted a 3-month prospective study investigating antipsychotic adherence with EAM (eCAP® ). Participants were treated with different oral antipsychotics, including clozapine, and blind to EAM monitoring; all were on antipsychotic monotherapy administered once daily. Outcome measures included adherence rate, missed dose, and medication gap. Adherence trajectory patterns were also analyzed for clozapine vs. other antipsychotics collectively. RESULTS: A total of 111 patients were included in the study; 33 and 78 patients received clozapine or other antipsychotics, respectively. Adherence rates, defined as proportion of days that the subject took the medication at the prescribed time ± 3 h and proportion of subjects with ≥80% adherence, were numerically higher in patients receiving clozapine vs. other antipsychotics (72.0% vs. 65.1%, P = 0.10; 49.5% vs. 35.7%, P = 0.11, respectively). Along similar lines, some of the missed dose and medication gap outcomes were significantly better in patients receiving clozapine vs. other antipsychotics. Three adherence trajectory patterns were identified for both clozapine and other antipsychotics, with two shared by both groups (i.e., low adherence with a slight decrease over time; high and stable adherence). CONCLUSION: Findings suggest that in patients with schizophrenia clozapine adherence is at least comparable, if not slightly better, compared with other antipsychotics.

Clozapine administration in clinical practice: once-daily versus divided dosing.

OBJECTIVE: While it is recommended that clozapine be administered in a divided dosing regimen, it is unclear whether this recommendation is followed in real-world clinical practice. In two large datasets, we examined clozapine dosing frequency and patient characteristics across different dosing regimens. METHOD: We conducted a cross-sectional survey, collecting data on patients receiving clozapine in August/September 2015 from the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, and The Zucker Hillside Hospital (ZHH) in New York, United States. RESULTS: Of 676 and 308 patients included in CAMH and ZHH datasets, clozapine was prescribed once daily in 75.1% and 74.4%, even though doses exceeding 200 mg/day were administered in 88.6% and 84.4% of the respective samples. No significant difference was found in the rates of positive symptom remission between once-daily vs. divided dosing (79.7% vs. 80.5%, P = 1.00). Higher clozapine dose and use of anticholinergic medications were significantly associated with divided dosing in both datasets. Older age or male gender was related to divided dosing in CAMH or ZHH dataset respectively. CONCLUSION: Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia.

OBJECTIVE: Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one-year longitudinal functional outcomes in patients with schizophrenia. METHOD: The sample included 754 patients with schizophrenia who completed both baseline and one-year follow-up visits in the CATIE study. Patients were evaluated with a comprehensive battery of assessments capturing symptom severity and cognitive performance among other variables. The primary outcome variable was functional status one-year postbaseline measured using the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Factor analysis of negative symptom items revealed two factors reflecting diminished expression and amotivation. Multivariate regression modeling revealed several significant independent predictors of longitudinal functioning scores. The strongest predictors were baseline amotivation and neurocognition. Both amotivation and neurocognition also had independent predictive value for each of the domains of functioning assessed (e.g., vocational). CONCLUSION: Both motivational and neurocognitive deficits independently contribute to longitudinal functional outcomes assessed 1 year later among patients with schizophrenia. Both of these domains of psychopathology impede functional recovery; hence, it follows that treatments ameliorating each of these symptoms should promote community functioning among individuals with schizophrenia.

The different trajectories of antipsychotic response: antipsychotics versus placebo.

BACKGROUND: It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response. METHOD: We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different. RESULTS: Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories ('Partial responder' and 'Responder') accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug-placebo difference was in the 'Dramatic responders', seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories. CONCLUSIONS: Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The 'Dramatic responders' (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug-placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action.

Clozapine's critical role in treatment resistant schizophrenia: ensuring both safety and use.

INTRODUCTION: Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring. AREAS COVERED: An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates. EXPERT OPINION: Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Motivated to do well: an examination of the relationships between motivation, effort, and cognitive performance in schizophrenia.

The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients.

Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder.

BACKGROUND: There is considerable comorbidity of major depression and posttraumatic stress disorder (PTSD), and antidepressants have been reported to be effective in treating PTSD. Addition of triiodothyronine (T3) to ongoing antidepressant treatment is considered an effective augmentation strategy in refractory depression. We report the effect of T3 augmentation of antidepressants in patients with PTSD. METHOD: T3 (25 microg/day) was added to treatment with a selective serotonin reuptake inhibitor (SSRI) (paroxetine or fluoxetine, 20 mg/day for at least 4 weeks and 40 mg/day for a further 4 weeks) of 5 patients who fulfilled DSM-IV criteria for PTSD but not for major depressive disorder (although all patients had significant depressive symptoms). The Clinician-Administered PTSD Scale, the 21-item Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Severity of Illness scale were administered every 2 weeks, and self-assessments were performed with a 100 mm visual analog mood scale. RESULTS: In 4 of the 5 patients, partial clinical improvement was observed with SSRI treatment at a daily dose of 20 mg with little further improvement when the dose was raised to 40 mg/day. This improvement was substantially enhanced by the addition of T3. Improvement was most striking on the Hamilton Rating Scale for Depression. CONCLUSION: T3 augmentation of SSRI treatment may be of therapeutic benefit in patients with PTSD, particularly those with depressive symptoms. Larger samples and controlled studies are needed in order to confirm this observation.

Environmental stress and psychiatric illness.

It has long been recognized that environmental stress plays a pivotal role in the pathogenesis of psychiatric disorders. The relationship is complex and the neurobiological mechanisms that mediate the contribution of stressful experiences to the manifestation of illness are not well understood. In considering this relationship, it is important to differentiate between the role of environmental stressors as vulnerability factors that predispose the individual to psychiatric illness and may be temporally distant from its clinical onset, and their role as direct precipitants of the illness. Furthermore, environmental stressors must be considered in the context of constitutional vulnerability factors, such as genetic predisposition, with which such stressors may interact. Genetic predisposition may influence not only vulnerability to illness but also the nature of the individual's response to stress and the likelihood of exposure to stressful events. In this paper, we focus on two areas that illustrate the complexity of the field and the important findings that have emerged--the role of early parental loss (EPL) in adult psychopathology, particularly major depression, and the relationship between recent significant life events and depressive episodes. We conclude with a preliminary conceptual framework for considering the relationship between genetic susceptibility and environmental stress in the pathogenesis of psychiatric illness.

Impact of primary negative symptoms on functional outcomes in schizophrenia.

OBJECTIVE: Negative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia. METHOD: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Negative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients. CONCLUSIONS: Primary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery.

Prediction of longitudinal functional outcomes in schizophrenia: the impact of baseline motivational deficits.

Emerging evidence suggests that motivational deficits are a central component of negative symptoms in schizophrenia, and linked to functional impairment characterizing this illness. This study extends previous cross-sectional findings by examining the concurrent contributions of baseline motivational deficits, other negative symptoms, and other symptom domains on longitudinal functional outcomes in schizophrenia. Results of this longitudinal examination of 18 patients from our previous pilot study reveal that amotivation accounts for 74% and 72% of the variance in functional outcomes at baseline and 6-month follow-up, respectively. These findings further suggest a fundamental role for motivational deficits in predicting functional outcomes in schizophrenia.

The impact of parental death versus separation from parents on the mental health of Israeli adolescents.

Early research suggested that the loss of a parent during childhood can lead to depression and other psychopathology in children and adults. More recent research has differentiated between loss due to death and separation from parents and has questioned the link between early parental death and psychopathology. We examined the hypothesis that separation from parents has a more detrimental effect than the death of a parent on the mental health of adolescents in the community. Israeli adolescents (N = 844) with a mean age of 16.7 +/- 1.0 years (mean +/- SD) participated in this study. Seventy reported that a parent did not live at home during one of three 5-year periods until they reached the age of 15; 37 reported the death of a parent and 777 were from intact families. All participants completed the Brief Symptom Inventory (BSI), General Well Being Schedule (GWB), Parental Bonding Instrument (PBI), and Perceived Social Support Family/ Friends Scales (PSS-Fam and PSS-Fr). Adolescents who had experienced separation from parents had more psychiatric symptoms (BSI), expressed a lower sense of well-being (GWB), experienced less support from their family (PSS-Fam), and felt less cared for and more controlled by their parents (PBI) compared with those belonging to intact families. The death of a parent was not associated with significantly different scores on these variables. When we controlled for parental bonding (PBI) and perceived social support from family (PSS-Fam), the differences between the separation group and the intact family group were no longer significant. The psychological impact of separation from parents involves a greater risk for psychopathology than the death of a parent. The quality of the relationship with the parents moderates the negative impact of separation from them.

Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia.

The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.

Increased prevalence of negative life events in subtypes of major depressive disorder.

The prevalence of negative life events is known to be increased among patients with depression. Little data exist on the specific subtypes of depression that are related to negative life events. Our study aimed to address this issue. We compare 115 patients with major depressive disorder (MDD) to 60 normal controls. MDD patients reported experiencing one (P = .0001) or two (P = .01) negative life events more frequently than controls. Patients reported marital, other personal problems, and medical events significantly more often than controls (P < .01). Patients did not report more positive life events, and did not attribute greater severity to their adversities than controls. Younger MDD patients experienced four (P = .01) negative life events significantly more often than older patients. Similarly, patients with mild-moderate depression, nonmelancholic depression, or first episode of depression (FDE), respectively, experienced three or four life events significantly more often than patients with severe, melancholic, or recurrent depression (RDE). Other patient and illness characteristics such as gender, early parental loss, family history of depression or other mental disorders, psychotic features, suicide attempts, and chronicity were not related to increased prevalence of negative life events. Our results support the hypothesis that a subset of patients with MDD is especially prone to suffer from a cluster of negative life events. This subgroup is at increased risk for relapse and poor prognosis. The implications of these results for further research and for treatment are discussed.