Barnaby Nelson

Comorbid Depressive and Anxiety Disorders in 509 Individuals With an At-Risk Mental State: Impact on Psychopathology and Transition to Psychosis

Background: The current diagnostic system for subjects at enhanced clinical risk of psychosis allows concurrent comorbid diagnoses of anxiety and depressive disorders. Their impact on the presenting high-risk psychopathology, functioning, and transition outcomes has not been widely researched. Methods: In a large sample of subjects with an At-Risk Mental State (ARMS, n = 509), we estimated the prevalence of DSM/SCID anxiety or depressive disorders and their impact on psychopathology, functioning, and psychosis transition. A meta-analytical review of the literature complemented the analysis. Results: About 73% of ARMS subjects had a comorbid axis I diagnosis in addition to the “at-risk” signs and symptoms. About 40% of ARMS subjects had a comorbid diagnosis of depressive disorder while anxiety disorders were less frequent (8%). The meta-analysis conducted in 1683 high-risk subjects confirmed that baseline prevalence of comorbid depressive and anxiety disorders is respectively 41% and 15%. At a psychopathological level, comorbid diagnoses of anxiety or depression were associated with higher suicidality or self-harm behaviors, disorganized/odd/stigmatizing behavior, and avolition/apathy. Comorbid anxiety and depressive diagnoses were also associated with impaired global functioning but had no effect on risk of transition to frank psychosis. Meta-regression analyses confirmed no effect of baseline anxiety and/or depressive comorbid diagnoses on transition to psychosis. Conclusions: The ARMS patients are characterized by high prevalence of anxiety and depressive disorders in addition to their attenuated psychotic symptoms. These symptoms may reflect core emotional dysregulation processes and delusional mood in prodromal psychosis. Anxiety and depressive symptoms are likely to impact the ongoing psychopathology, the global functioning, and the overall longitudinal outcome of these patients.

Intervention in individuals at ultra high risk for psychosis : a review and future directions

OBJECTIVE Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. DATA SOURCES A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. STUDY SELECTION All published intervention trials with ultra-high-risk cohorts. DATA SYNTHESIS The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. CONCLUSIONS Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Long-term Follow-up of a Group at Ultra High Risk (“Prodromal”) for Psychosis: The PACE 400 Study

IMPORTANCE The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. OBJECTIVE To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. DESIGN Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. SETTING The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. PARTICIPANTS Four hundred sixteen UHR patients previously seen at the PACE clinic. MAIN OUTCOMES AND MEASURES Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. RESULTS During the time to follow-up (2.4-14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. CONCLUSIONS AND RELEVANCE The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated.

Psychotic-like experiences in a community sample of adolescents: implications for the continuum model of psychosis and prediction of schizophrenia

Objective: Studies conducted in community samples suggest that psychotic-like experiences are common in the general population, leading to suggestions that they are either variations of normal personality or are different expressions of underlying vulnerability to psychotic disorder. Different types of psychotic symptoms may exist, some being normal variants and some having implications for mental health and functioning. The aim of the present study was to determine if different subtypes of psychotic-like experiences could be identified in a community sample of adolescents and to investigate if particular subtypes were more likely to be associated with psychosocial difficulties, that is, distress, depression and poor functioning, than other subtypes. Method: Eight hundred and seventy-five Year 10 students from 34 schools participated in a cross-sectional survey that measured psychotic-like experiences using the Community Assessment of Psychic Experiences; depression using the Centre for Epidemiologic Studies Depression Scale; and psychosocial functioning using the Revised Multidimensional Assessment of Functioning Scale. Factor analysis was conducted to identify any subtypes of psychotic experiences. Results: Four subtypes of psychotic-like experiences were identified: Bizarre Experiences, Perceptual Abnormalities, Persecutory Ideas, and Magical Thinking. Intermittent, infrequent psychotic experiences were common, but frequent experiences were not. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas were strongly associated with distress, depression and poor functioning. Magical Thinking was only weakly associated with these variables. Overall these findings may suggest that infrequent psychotic-like experiences are unlikely to be a specific risk factor for onset of a psychotic disorder in community samples. Conclusions: Given that the different subtypes had varying associations with current difficulties it is suggested that not all subtypes confer the same risk for onset of psychotic disorder and poor outcome. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas may represent expressions of underlying vulnerability to psychotic disorder, but Magical Thinking may be a normal personality variant.

Psychotic-like experiences and correlation with distress and depressive symptoms in a community sample of adolescents and young adults

OBJECTIVE Studies conducted in community samples indicate that psychotic-like experiences (PLEs) are common in the general population; it has been suggested that such experiences are either variations in normal personality or different expressions of vulnerability to psychotic disorders. The aim of this study was to determine whether different subtypes of PLEs could be identified in a community sample of adolescents and young adults, and to investigate whether particular subtypes of PLEs were more likely to be associated with psychosocial difficulties, i.e. distress, depression and poor functioning, than other subtypes. METHOD 1882 students from high schools and universities participated in a cross-sectional multisite survey that measured i) PLEs using the Positive Scale of the Community Assessment of Psychic Experiences (CAPE), ii) depression and distress using the CAPE Depression and Distress Subscales, and iii) functioning using the General Health Questionnaire-12. Factor analysis was conducted to identify any subtypes of PLEs. RESULTS Four subtypes of PLEs were identified: bizarre experiences (BE), perceptual abnormalities (PA), persecutory ideas (PI) and grandiosity (GR). Intermittent, infrequent psychotic experiences were common, whereas frequent experiences were not. BE and PI were strongly associated with distress, depression and poor functioning. PA and GR were associated with these variables to a lesser degree. CONCLUSIONS Different subtypes of PLEs were identified in this large sample, confirming the findings of our previous studies. These subtypes seem to have different psychopathological meaning and may therefore indicate different levels of risk of severe psychiatric disorders, which suggests it is misleading to define PLEs as a homogenous entity.

Anatomic abnormalities of the anterior cingulate cortex before psychosis onset: an MRI study of ultra-high-risk individuals.

BACKGROUND Abnormalities of the anterior cingulate cortex (ACC) are frequently implicated in the pathophysiology of psychotic disorders, but whether such changes are apparent before psychosis onset remains unclear. In this study, we characterized prepsychotic ACC abnormalities in a sample of individuals at ultra-high-risk (UHR) for psychosis. METHODS Participants underwent baseline magnetic resonance imaging and were followed-up over 12-24 months to ascertain diagnostic outcomes. Baseline ACC morphometry was then compared between UHR individuals who developed psychosis (UHR-P; n = 35), those who did not (UHR-NP; n = 35), and healthy control subjects (n = 33). RESULTS Relative to control subjects, UHR-P individuals displayed bilateral thinning of a rostral paralimbic ACC region that was negatively correlated with negative symptoms, whereas UHR-NP individuals displayed a relative thickening of dorsal and rostral limbic areas that was correlated with anxiety ratings. Baseline ACC differences between the two UHR groups predicted time to psychosis onset, independently of symptomatology. Subdiagnostic comparisons revealed that changes in the UHR-P group were driven by individuals subsequently diagnosed with a schizophrenia spectrum psychosis. CONCLUSIONS These findings indicate that anatomic abnormalities of the ACC precede psychosis onset and that baseline ACC differences distinguish between UHR individuals who do and do not subsequently develop frank psychosis. They also indicate that prepsychotic changes are relatively specific to individuals who develop a schizophrenia spectrum disorder, suggesting they may represent a diagnostically specific risk marker.

Neurocognitive predictors of functional outcome two to 13 years after identification as ultra-high risk for psychosis

BACKGROUND AND AIM Little is known about the relationship between neurocognitive performance and functional outcome before the onset of frank psychosis. This longitudinal study aimed to investigate neurocognitive predictors of poor functional outcome in a group identified as ultra-high risk (UHR) for psychosis between two and 13 years prior. METHOD Individuals (N=230) identified as UHR for psychosis at the PACE Clinic in Melbourne completed assessment of psychopathology, functioning and neurocognition at baseline and follow-up. The mean length of follow-up was 7.26 years (SD 3.05). RESULTS Forty-one individuals with the poorest functional outcome were identified. Only 48.8% of this group had transitioned to psychosis. Poor functional outcome was associated with reduced performance at baseline in the specific neurocognitive domains of verbal learning and memory, processing speed and attention, and verbal fluency, but not global cognitive impairment. Reduced performance on a verbal story recall task, in combination with higher negative symptoms at baseline, was the best predictor of later poor outcome. Baseline positive psychotic symptoms and GAF scores were not associated with later poor outcome. DISCUSSION To date, this is the longest follow-up study of an UHR sample. Poor functional outcome was associated with specific neurocognitive decrements, regardless of transition to psychosis. The detection of individuals with poor functioning at follow-up, against a background of previously identified risk factors for psychotic disorder, may yield a valid group in which to study biomarkers and treatment of schizophrenia.

Clinical staging: A heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders

Most mental illnesses emerge during adolescence and early adulthood, with considerable associated distress and functional decline appearing during this critical developmental phase. Our current diagnostic system lacks therapeutic validity, particularly for the early stages of mental disorders when symptoms are still emerging and intensifying and have not yet stabilized sufficiently to fit the existing syndromal criteria. While this is, in part, due to the difficulty of distinguishing transient developmental or normative changes from the early symptoms of persistent and disabling mental illness, these factors have contributed to a growing movement for the reform of our current diagnostic system to more adequately inform the choice of therapeutic strategy, particularly in the early stages of a mental illness. The clinical staging model, which defines not only the extent of progression of a disorder at a particular point in time but also where a person lies currently along the continuum of the course of an illness, is particularly useful as it differentiates early, milder clinical phenomena from those that accompany illness progression and chronicity. This will not only enable clinicians to select treatments relevant to earlier stages of an illness, where such interventions are likely to be more effective and less harmful than treatments delivered later in the course of illness, but also allow a more efficient integration of our rapidly expanding knowledge of the biological, social, and psychological vulnerability factors involved in the development of mental illness into a useful diagnostic framework.

Experience of trauma and conversion to psychosis in an ultra-high-risk (prodromal) group.

Bechdolf A, Thompson A, Nelson B, Cotton S, Simmons MB, Amminger GP, Leicester S, Francey SM, McNab C, Krstev H, Sidis A, McGorry PD, Yung AR. Experience of trauma and conversion to psychosis in an ultra‐high‐risk (prodromal) group.

Emotion Recognition in Individuals at Clinical High-Risk for Schizophrenia

Problems in the perception of emotional material, in particular deficits in the recognition of negative stimuli, have been demonstrated in schizophrenia including in first-episode samples. However, it is largely unknown if emotion recognition impairment is present in people with subthreshold psychotic symptoms. Here, we examined the capacity to recognize facially expressed emotion and affective prosody in 79 individuals at ultra high-risk for psychosis, 30 clinically stable individuals with first-episode schizophrenia assessed as outpatients during the early recovery phase of illness, and 30 unaffected healthy control subjects. We compared (1) scores for a combined fear-sadness aggregate index across face and voice modalities, (2) summary scores of specific emotions across modalities, and (3) scores for specific emotions for each sensory modality. Findings supported deficits in recognition of fear and sadness across both modalities for the clinical groups (the ultra high-risk and first-episode group) as compared with the healthy controls. Furthermore, planned contrasts indicated that compared with the healthy control subjects, both clinical groups had a significant deficit for fear and sadness recognition in faces and for anger recognition in voices. Specific impairments in emotion recognition may be apparent in people at clinical high-risk for schizophrenia before the full expression of psychotic illness. The results suggest a trait deficit and an involvement of the amygdala in the pathology of ultra high-risk states.