Scott R. Clark

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Psychobiological heterogeneity of familial and sporadic schizophrenia

BACKGROUND Although schizophrenia is presumed to be heterogeneous, there has been limited success distinguishing familial from sporadic cases. We used psychobiological measures to examine heterogeneity, as they may be closer to neurobiology than symptoms. Smooth pursuit eye movement quality (SPEM) and dichotic listening (DL) tests to tones and words were used to assess hemispheric laterality asymmetry. METHODS Forty-six research unit patients participated in assessments of family history (FH) and physiological measures. FH was categorized by three exclusive groups: FH-1 patients had a chronic schizophrenia-related psychosis in a first-degree relative, FH-2 had it in second-degree relative, and FH-3 had no family member with a reoccurrence. RESULTS Analysis of variance showed a significant group difference for SPEM and DL tones. SPEM was significantly worse in all three schizophrenia groups than for the normal comparison subjects. Among the schizophrenia groups, the nonfamilial group (FH-3) had the worst SPEM quality, FH-2 had intermediate quality, and FH-1 had the best quality. Conversely, only the nonfamilials (FH-3) had normal right hemispheric lateralization for tones, whereas familials did not, and FH-2 again had intermediate values. The lateralization quotient for DL words did not significantly differ among the groups. CONCLUSIONS SPEM was affected most in sporadic, not familial schizophrenia, whereas dichotic listening was most affected in familial schizophrenia. This double dissociation supports the utility of the familial/sporadic distinction and suggests that etiological factors in different forms of schizophrenia may impact principally on distinct neurobiological substrates, despite similar patient phenomenology.

Towards indicated prevention of psychosis: using probabilistic assessments of transition risk in psychosis prodrome

The concept of indicated prevention has proliferated in psychiatry, and accumulating evidence suggests that it may indeed be possible to prevent or delay the onset of a first episode of psychosis though adequate interventions in individuals deemed at clinical high risk (CHR) for such an event. One challenge undermining these efforts is the relatively poor predictive accuracy of clinical assessments used in practice for CHR individuals, often leading to diagnostic and therapeutic uncertainty reflected in clinical guidelines promoting a ‘watch and wait’ approach to CHR patients. Using data from published studies, and employing predictive models based on the odds-ratio form of Bayes’ rule, we simulated scenarios where clinical interview, neurocognitive testing, structural magnetic resonance imaging and electrophysiology are part of the initial assessment process of a CHR individual (extended diagnostic approach). Our findings indicate that for most at-risk patients, at least three of these assessments are necessary to arrive at a clinically meaningful differentiation into high- intermediate-, and low-risk groups. In particular, patients with equivocal results in the initial assessments require additional diagnostic testing to produce an accurate risk profile forming part of the comprehensive initial assessment. The findings may inform future research into reliable identification and personalized therapeutic targeting of CHR patients, to prevent transition to full-blown psychosis.

The use of clinical and biological characteristics to predict outcome following First Episode Psychosis

Objective: Psychotic illnesses such as schizophrenia and other non-affective psychoses are heterogeneous in disease course and functional outcomes. We review evidence from investigations in clinical psychiatry, neuroimaging, neurocognition, and blood biomarker research suggesting that distinct bio-psycho-social patterns exist at the onset and during the early phase of a First Episode Psychosis (FEP), which can describe the risk of individual illness progression and functional trajectories. Method: A selective literature review was performed on articles drawn from Medline searches for relevant key words. A simulation model was constructed from data derived from two recent publications, selected as examples of studies that investigated multivariate predictors of long-term outcome following FEP. Results: We illustrate how illness trajectories following FEP could be described based on multimodal sociodemographic, clinical, psychological, and neurobiological information. A clinical modeling simulation shows thatrisk trajectories for achieving long-term favorable or unfavorable outcomes can differ significantly depending on baseline characteristics in combination with MRI and functional measurements within 6 months of disease onset. Conclusions: Multimodal trajectory modeling may be useful to describe longitudinal outcomes following FEP. Richlongitudinal data on predictors and outcomes, and better integration of multimodal (sociodemographic, clinical, psychological, biological) data, are required to operationalize this approach. This technique may improve our understanding of course of illness and help to provide a more personalized approach to the assessment and treatment of people presenting with FEP.

Depressive symptom trajectories in late adolescence and early adulthood: A systematic review:

Objective: In adolescents and young adults, depressive symptoms are highly prevalent and dynamic. For clinicians, it is difficult to determine whether a young person reporting depressive symptoms is at risk of developing ongoing mood difficulties or whether symptoms form part of a transient maturational process. Trajectory analyses of longitudinally assessed symptoms in large cohorts have the potential to untangle clinical heterogeneity by determining subgroups or classes of symptom course and their risk factors, by interrogating the impact of known or suspected risk factors on trajectory slope and intercept and by tracing the interrelation between depressive symptoms and other clinical outcomes over time. Method: We conducted a systematic review of trajectory studies conducted in cohorts including people aged between 15 and 25 years. Results: We retrieved 47 relevant articles. These studies suggest that young people fall into common mood trajectory classes and that class membership and symptom course are mediated by biological and environmental risk factors. Furthermore, studies provide evidence that high and persistent depressive symptoms are associated with a range of concurrent health and behavioral outcomes. Conclusion: Findings could assist in the formulation of novel concepts of depressive disorders in young people and inform preventive strategies and predictive models for clinical practice.

In-vivo administration of clozapine affects behaviour but does not reverse dendritic spine deficits in the 14-3-3ζ KO mouse model of schizophrenia-like disorders.

Clozapine is an atypical antipsychotic drug used in the treatment of schizophrenia, which has been shown to reverse behavioural and dendritic spine deficits in mice. It has recently been shown that deficiency of 14-3-3ζ has an association with schizophrenia, and that a mouse model lacking this protein displays several schizophrenia-like behavioural deficits. To test the effect of clozapine in this mouse model, 14-3-3ζ KO mice were administered clozapine (5mg/kg) for two weeks prior to being analysed in a test battery of cognition, anxiety, and despair (depression-like) behaviours. Following behavioural testing brain samples were collected for analysis of specific anatomical defects and dendritic spine formation. We found that clozapine reduced despair behaviour of 14-3-3ζ KO mice in the forced swim test (FST) and altered the behaviour of wild types and 14-3-3ζ KO mice in the Y-maze task. In contrast, clozapine had no effects on hippocampal laminar defects or decreased dendritic spine density observed in 14-3-3ζ KO mice. Our results suggest that clozapine may have beneficial effects on clinical behaviours associated with deficiencies in the 14-3-3ζ molecular pathway, despite having no effects on morphological defects. These findings may provide mechanistic insight to the action of this drug.

Late onset myocarditis with clozapine use.

Myocarditis is a serious complication of clozapine therapy with a reported incidence between 0.7% to 1.2% (Layland et al., 2009). The majority of cases occur within two months of commencement (Layland et al., 2009) with occasional reports after long-term therapy (Lang et al., 2008). The exact mechanism underlying clozapine-related myocarditis is unknown. Hypotheses include: IgEmediated hypersensitivity, increased plasma catecholamine, cytochrome P450 1A2 enzyme deficiency, blockade of calcium-dependent ion channels, increased production of inflammatory cytokines, and low serum selenium levels (Layland et al., 2009). We report two cases of myocarditis after long-term clozapine therapy identified during routine monitoring. Mr R, a 62-year-old male nursing home resident, was treated with clozapine (500mg/day) from 1997 for schizophrenia. He has a background of diabetes, hyperlipidaemia and peripheral vascular disease. He presented with lethargy, temperature of 38.3o C, CRP 200mg/L and troponin T 276ng/L. Serial ECG showed T wave inversion with variable broadening of QRS complex. His echocardiogram revealed moderate systolic dysfunction and ejection fraction of 33% with global hypokinesis. A diagnosis of clozapineinduced myocarditis was made after excluding alternative aetiologies. Clozapine was ceased and he was commenced on olanzapine 5mg. He made good clinical recovery and was discharged two weeks later but died seven weeks later due to renal failure. Mr S, a 52-year-old male with a 24-year history of schizophrenia was treated on 500mg/day of clozapine since 2009. His clozapine levels ranged from 146-910μg/L suggesting longterm partial compliance. His medical history includes hyperlipidaemia and diabetes. He presented with a twoweek history of exertional dyspnoea without chest pain. ECG showed new onset atrial flutter 2:1 with sinus tachycardia, troponin T 294ng/L, CRP 25mg/L. Echocardiogram revealed systolic dysfunction with an ejection fraction of 35% and global hypokinesis. He was diagnosed with myocarditis secondary to clozapine. Clozapine was ceased, and olanzapine 10mg was initiated. He was discharged home one week later following clinical recovery. His cardiac condition remains stable four months after discharge. These cases meet the criteria for clozapine-related myocarditis but occur outside the initial high-risk period following commencement (Ronaldson et al., 2010) suggesting the need for ongoing clinical vigilance for symptoms suggestive of myocarditis for the duration of clozapine treatment. Suspicion should lead to prompt investigation with troponin T, CRP and ECG to facilitate early identification and treatment of myocarditis.

A state-wide quality improvement system utilising nurse-led clinics for clozapine management:

Objectives: This paper describes the implementation of a state-wide clozapine management system to improve the quality of care for those with treatment-resistant schizophrenia. This intervention includes standardised forms, computer-based monitoring and alerting and nurse-led clinics for stable consumers. Methods: Methods used during system development included medical record and clinical information system audit, consensus review of available evidence and qualitative review of existing forms, systems and stakeholder opinion. Results: Nurse-led monitoring safely reduced medical outpatient appointments by 119 per week in metropolitan public clinics. In the 15 months following the implementation of all interventions, mortality associated with physical illness not related to malignancy was reduced from an average of 5 deaths per year to one. Conclusions: Differing interpretations of clozapine guidelines have contributed to confusion around monitoring. Standardised documentation has helped to increase understanding and improve protocol adherence. A regular training programme has increased basic knowledge of risks and protocols. Computer-based documentation and alerting systems have improved communication between hospital and community-based teams and prompted early intervention reducing the risk of adverse events. These factors have combined to help improve outcomes in clozapine management. Nurse-led clinics are a safe and efficient alternative for monitoring clozapine treatment.

Elevated clozapine levels associated with infection: A systematic review

Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.

Trajectories of anxiety and health related quality of life during pregnancy

Anxiety and health related Quality of Life (HRQoL) have emerged as important mental health measures in obstetric care. Few studies have systematically examined the longitudinal trajectories of anxiety and HRQoL in pregnancy. Using a linear growth modeling strategy, we analyzed the course of State-Trait Anxiety Inventory (STAI)- and Short Form (36) Health Survey (SF-36) scores between the 12th and the 36th week of gestation, in a sample of 355 women. We additionally analyzed the impact of depressive symptoms and a chronic medical condition (asthma), on STAI and SF-36 trajectory curves. STAI scores remained stable throughout pregnancy. A previous history of anxiety increased the overall STAI scores. Asthma and depressive symptoms scores had no impact on the STAI trajectory. Physical SF-36 scores decreased over the course of pregnancy, whereas mental SF-36 trended towards improvement. Asthma reduced physical SF-36 overall. While high depressive symptoms decreased the overall mental SF-36, they were also significantly associated with mental SF-36 improvements over time. Anxiety symptoms are stable during pregnancy and are not modulated by depressive symptoms or asthma. Physical HRQoL declines in pregnancy. In contrast, mental HRQoL appears to improve, particularly in women with high initial levels of depressive symptoms.