Kathryn Eve Lewandowski

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Verified

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• Ph.D.
• Professor (Associate) at Harvard Medical School

Introduction Motivational impairments are a hallmark symptom of psychotic disorders. However, motivation is a multidimensional construct believed to be underpinned by different neural mechanisms and differentially impaired both between and within diagnostic groups. We used a data driven approach to identify different motivational profiles in people...

Cognitive dysfunction is a core dimension in psychotic disorders and among the strongest predictors of disability and poor quality of life. Cognitive impairments are highly heterogeneous, and cross‐sectional studies have consistently found evidence of distinct cognitive profiles both within diagnoses and transdiagnostically. Findings regarding the...

The Accelerating Medicines Partnership Schizophrenia (AMP® SCZ) program integrates lived experience into psychosis research, leveraging over three decades of foundational studies to improve research quality, promote community engagement, and ensure ethical implementation of precision psychiatry. Lived experience is embedded in the program’s governa...

The Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ) project assesses a large sample of individuals at clinical high-risk for developing psychosis (CHR) and community controls. Subjects are enrolled in 43 sites across 5 continents. The assessments include domains similar to those acquired in previous CHR studies along with novel domains...

Modern research management, particularly for publicly funded studies, assumes a data governance model in which grantees are considered stewards rather than owners of important data sets. Thus, there is an expectation that collected data are shared as widely as possible with the general research community. This presents problems in complex studies t...

Clinical ascertainment and clinical outcome are key features of any large multisite study. In the ProNET and PRESCIENT research networks, the Accelerating Medicines Partnership® Schizophrenia (AMP®SCZ) Clinical Ascertainment and Outcome Measures Team aimed to establish a harmonized clinical assessment protocol across these two research networks and...

Cognitive impairment occurs at higher rates in individuals at clinical high risk (CHR) for psychosis relative to healthy peers, and it contributes unique variance to multivariate prediction models of transition to psychosis. Such impairment is considered a core biomarker of schizophrenia. Thus, cognition is a key domain measured in the Accelerating...

Objective Children at familial high risk for psychosis (FHR) are at substantially increased risk for psychotic disorders and other serious mental illnesses. Identifying risk subgroups within FHR youth may enhance prediction models to identify children at greatest risk for potential intervention. This study investigated psychosis-linked symptoms and...

Background and Hypothesis Convergent evidence shows the presence of brain metabolic abnormalities in psychotic disorders. This study examined brain reductive stress and energy metabolism in people with psychotic disorders with impaired or average range cognition. We hypothesized that global cognitive impairment would be associated with greater brai...

Background: Given that protein expression mediates genetic vulnerability, proteomics—the comprehensive study of proteins—is regaining prominence in neuropsychiatric research. This resurgence is driven by novel technical advancements that enable the simultaneous examination of multiple proteins. Numerous studies have demonstrated the potential of pr...

Background The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Ps...

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analy...

Background and Hypothesis Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strat...

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of...

Background Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of...

Background Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. Methods This 20-year fol...

Background Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain dif...

The choroid plexus (ChP) is part of the blood‐cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging‐b...

Background Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain dif...

Background: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neu...

In people with schizophrenia and related disorders, impairments in communication and social functioning can negatively impact social interactions and quality of life. In the present study, we investigated the cognitive basis of a specific aspect of linguistic communication—lexical alignment—in people with schizophrenia and bipolar disorder. We prob...

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expr...

The early stage of psychosis (ESP) is a critical period where effective intervention has the most favorable impact on outcomes. Thalamic connectivity abnormalities have been consistently found in psychosis, and are associated with clinical symptoms and cognitive deficits. However, most studies consider ESP patients as a homogeneous population and f...

Background: Cognitive impairments are an emerging treatment target in mood disorders but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provid...

Motivational and perceptual disturbances co-occur in psychosis and have been linked to aberrations in reward learning and sensory gating, respectively. Although traditionally studied independently, when viewed through a predictive coding framework, these processes can both be linked to dysfunction in striatal dopaminergic prediction error signaling...

Psychiatric diagnosis is often treated as a stable construct both clinically and in research; however, some evidence suggests that diagnostic change may be common, which may impact research validity and clinical care. In the present study we examined diagnostic stability in individuals with psychosis over time. Participants with a diagnosis of any...

Introduction Recent studies show that sleep favors oligodendrocyte proliferation and myelination, and sleep loss is associated with alterations in white matter structure and decreased myelination. Psychotic disorders are characterized by disrupted white matter integrity, and abnormal axon and myelin structure. Despite common sleep disturbances in t...

Background Reduced mismatch negativity (MMN) is observed in early psychosis (EP) and correlated with cognition and functioning, but few studies have examined their longitudinal relationships and diagnostic specificity. We examined MMN, neuro- and social-cognition, and functional measures in EP patients with schizophrenia-spectrum (SZ) or bipolar di...

Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and...

Recent theoretical models propose that abnormal effort-cost decision-making (ECDM) likely has divergent underpinnings across mood and psychotic disorders. However, whether this same model applies to individuals across the psychosis spectrum, including individuals with affective psychosis, remains unclear. This study aimed to empirically test whethe...

White matter (WM) abnormalities are commonly reported in schizophrenia but whether these arise from the axon or myelin compartments or both is not known. In addition, the relationship between WM abnormalities and cognitive function is not fully explored in this condition. We recruited 39 individuals with schizophrenia spectrum disorders and 37 heal...

Aim Cognitive remediation is an evidence‐based intervention targeting the common and disabling cognitive deficits in people with psychosis. Findings from efficacy studies and meta‐analyses show that cognitive remediation produces medium to large effects on cognition in both chronic and first episode patients. However, clinical availability of this...

Schizophrenia, bipolar disorder, and related psychotic illnesses are common, serious mental disorders that are often associated with functional impairments and poor quality of life, even after clinical recovery. Cognitive dysfunction is a strong predictor of functional impairment; however, findings regarding relative impairments in functioning and...

Psychotic disorders are severe, debilitating, and even fatal. The development of targeted and effective interventions for psychosis depends upon on clear understanding of the timing and nature of disease progression to target processes amenable to intervention. Strong evidence suggests early and ongoing neuroprogressive changes, but timing and infl...

The recently published debate article by Douglas et al. 20191 contends to introduce new terminology for therapeutic interventions on cognition in patients with major mood disorders. The authors argue that the commonly‐used term ‘cognitive remediation therapy’ does not capture the essence of the approaches that are currently being applied. We would...

Objectives: Cognitive dysfunction affects a significant proportion of people with bipolar disorder (BD), but the cause, trajectory and correlates of such dysfunction is unclear. Increased understanding of these factors is required to progress treatment development for this symptom dimension. Methods: This paper provides a critical overview of th...

Background: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably...

Background: White matter (WM) abnormalities are amongst the most commonly described neuroimaging findings in patients with psychotic disorders including schizophrenia (SZ) and bipolar disorder (BD), and may be central to pathophysiology. Few studies have directly compared WM abnormalities in patients with SZ and BD in the first episode of illness,...

Background Substantial cognitive heterogeneity exists both within and between diagnostic categories in patients with psychosis. Given that cognitive deficits are highly predictive of outcomes in patients and are believed to be underpinned by neurobiological abnormalities in relevant circuits, characterization of cognitive heterogeneity is a critica...

Background: Social cognitive ability is a significant determinant of functional outcome, and deficits in social cognition are a disabling symptom of psychotic disorders. The neurobiological underpinnings of social cognition are not well understood, hampering our ability to ameliorate these deficits. Objective: Using 'resting state' functional ma...

Background: Schizophrenia, schizoaffective disorder, and related illnesses are associated with significant impairment in cognitive functioning which is among the strongest predictors of disability and poor quality of life. Cognitive remediation (CR) was developed as a set of behavioral interventions directly targeting cognitive symptoms. Studies ha...

Bipolar Disorder (BD) is the 4th leading cause of disability worldwide among young people ages 10‐24 years. Although the diagnosis is largely defined by the mood episodes associated with the illness, cognitive deficits are among the most persistent and disabling symptoms of illness and have a profound impact on clinical course and functional outcom...

Cognitive dysfunction is common in many psychiatric disorders. While it has long been described as a core feature in schizophrenia, more recent data suggest qualitatively similar impairments in patients with bipolar disorder and major depressive disorder. There is compelling evidence to suggest that cognitive impairment contributes directly to func...

Background The visual system is recognized as an important site of pathology and dysfunction in schizophrenia. In this study, we evaluated different visual perceptual functions in patients with psychotic disorders using a potentially clinically applicable task battery and assessed their relationship with symptom severity in patients, and with schiz...

Background: Cognitive dysfunction is common in psychotic disorders, and may reflect underlying pathophysiology. However, substantial cognitive heterogeneity exists both within and between diagnostic categories, creating challenges for studying the neurobiology of cognitive dysfunction in patients. The aim of this study was to identify patients wit...

Objectives: Gamma oscillation is important for cortico-cortical coordination and the integration of information across neural networks. The 40 Hz auditory steady-state response (ASSR), which reflects neural synchrony in the gamma band (30-100 Hz), is abnormal in patients with schizophrenia (SZ). The present study used the ASSR at multiple frequenc...

Background Social cognitive ability is a significant determinant of functional outcome and deficits in social cognition are a disabling symptom of psychotic disorders. The neurobiological underpinnings of social cognition are not well understood, hampering our ability to ameliorate these deficits. Objective Using ‘resting-state’ fMRI (functional m...

Objectives: Cognitive dysfunction is a core symptom dimension that cuts across the psychoses. Recent findings support classification of patients along the cognitive dimension using cluster analysis; however, data-derived groupings may be highly determined by sampling characteristics and the measures used to derive the clusters, and so their interp...

Objective: Cognitive dysfunction is a core symptom dimension in bipolar disorder and a strong predictor of functional outcomes. Cognitive remediation (CR) produces moderate, durable effects on cognition in patients with schizophrenia; however, studies of CR in patients with bipolar disorder are sparse and findings have been mixed. Thus, the aim of...

Recently, the focus of funding mechanisms associated with clinical trials has changed to be consistent with an experimental therapeutics approach. While this approach holds considerable promise, the paradigm shift has presented challenges for behavioral trials in complex psychiatric illness such as schizophrenia, as molecular targets – the classic...

Background Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive...

Background: Cognitive deficits are well-documented in patients with bipolar disorder (BPD) and may impact the efficacy of psychotherapy. Cognitive control, a form of executive functioning, is often used therapeutically to shift patients' thoughts and behaviors from automatic, maladaptive responses to adaptive coping strategies. This study examined...

Objectives: A variety of treatment options exist for schizophrenia, but the effects of these treatments on brain function are not clearly understood. To facilitate the development of more effective treatment strategies, it is important to identify how brain function in schizophrenia patients is affected by the diverse therapeutic approaches that a...

We examined the effect of trait level grit on the experience of caregiver burden (CB) in a sample of 33 parents of patients in the OnTrack clinic for first-episode psychosis at McLean Hospital. Higher levels of grit were associated with reduced caregiver burden. We hope to explore the feasibility of extending interventions for bolstering grit to th...

Background Patients with psychosis spectrum disorders exhibit deficits in social and neurocognition, as well as hallmark abnormalities in motivation and reward processing. Aspects of reward processing may overlap behaviorally and neurobiologically with some elements of cognitive functioning, and abnormalities in these processes may share partially...

Cognitive dysfunction is a major feature of bipolar disorder with psychosis and is strongly associated with functional outcomes. Computer-based cognitive remediation has shown promise in improving cognition in patients with schizophrenia. However, despite similar neurocognitive deficits between patients with schizophrenia and bipolar disorder, few...

The development of cognitive remediation programs has been a key step toward the creation of a treatment approach to address the cognitive-symptom domain in psychosis. Studies support the efficacy of cognitive remediation in producing moderate effects on cognition at the group level in patients with schizophrenia. Cognitive remediation may harness...

Aims: Most programs specializing in the treatment of first-episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first-episode psychosis. Methods: We ass...

Given the substantial overlap in cognitive dysfunction between bipolar disorder (BD) and schizophrenia (SZ), we examined the utility of the MATRICS Consensus Cognitive Battery (MCCB)—developed for use in SZ—for the measurement of cognition in patients with BD with psychosis (BDP) and its association with community functioning. The MCCB, Multnomah C...

Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the “cognitive dysmetria” and “dysmetria of thought” models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral corte...

White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In th...

Both nonaffective and affective psychoses are associated with deficits in social functioning across the course of the illness. However, it is not clear how social functioning varies among diagnostic groups as a function of age. The current study examined the relationship between social functioning and age in schizophrenia (SZ), schizoaffective diso...

White matter (WM) abnormalities are among the most commonly reported neuroimaging findings in bipolar disorder. Nonetheless, the specific nature and pathophysiology of these abnormalities remains unclear. Use of a combination of magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) permits examination of myelin and axon abnorma...

Background: Cognitive dysfunction is a core feature of psychotic disorders; however, substantial variability exists both within and between subjects in terms of cognitive domains of dysfunction, and a clear ‘profile’ of cognitive strengths and weaknesses characteristic of any diagnosis or psychosis as a whole has not emerged. Cluster analysis provi...