David L. Fogelson

The structure of schizotypy: relationships between neurocognitive and personality disorder features in relatives of schizophrenic patients in the UCLA Family Study

Schizotypal personality features and certain neurocognitive deficits have been shown to aggregate in the relatives of schizophrenic patients, supporting the view that both are likely to reflect genetic contributions to liability to schizophrenia. Within the relatives of schizophrenic patients, however, the interrelationships between these potential indicators of liability to schizophrenia are not well known. Using data from the UCLA Family Study, we examine the interrelationships between personality disorder symptoms and neurocognitive functioning in nonpsychotic first-degree relatives of schizophrenic patients. Factor analyses indicate that several dimensions of schizotypy can be identified. A neurocognitive dysfunction dimension includes loadings from measures of sequential visual conceptual tracking, rapid perceptual encoding and search, and focused, sustained attention as well as the rating of odd and eccentric behavior from schizotypal personality disorder. Other aspects of schizotypal personality disorder form separate positive schizotypy and negative schizotypy dimensions. These analyses support the view that schizotypy is multidimensional in relatives of schizophrenic patients and indicate that neurocognitive deficits in perception and attention are associated with particular schizotypal personality features.

Interrater reliability of the structured clinical interview for DSM-III-R, Axis II: Schizophrenia spectrum and affective spectrum disorders

Three interviewers (second raters) blindly rated 15 audiotapes each of the Structured Clinical Interview for DSM-III-R, Axis II (SCID-II) administered to the first degree relatives of probands with either DSM-III-R schizophrenia, schizoaffective disorder, or bipolar disorder, for a total of 45 second ratings. Interrater reliability was determined using the intraclass correlation coefficient and ranged from 0.60 to 0.84. The previous studies of the reliability of structured interviews for diagnosing personality disorders are summarized and compared to the present findings. We conclude that the SCID-II can be reliably used to diagnose schizophrenia-spectrum and affective spectrum disorders in the first degree family members of probands with schizophrenic or bipolar affective disorders.

Testing Vulnerability Models: Stability of Potential Vulnerability Indicators Across Clinical State

In recent years, several researchers have proposed a distinction between vulnerability indicators (or markers) and episode indicators for schizophrenic disorders, based on whether an abnormality is present only during the active psychotic state or on a continuing basis (Zubin and Spring 1977; Cromwell and Spaulding 1978). Measures that reveal abnormalities during the acute psychotic episode and then return to normal levels during nonpsychotic, clinically remitted periods are called episode indicators, because they index processes that show acute disruptions during the psychotic period. Episode indicators would be expected to include (1) abnormalities that reflect processes immediately underlying the acute psychotic symptoms and (2) abnormalities that are secondary to disruptions associated with acute psychotic symptoms.

Persistence of fluphenazine in plasma after decanoate withdrawal

We discontinued fluphenazine decanoate using a double-blind, crossover random order design, in 12 recent onset clinically stable schizophrenics who had been given fluphenazine decanoate 12.5 mg intramuscularly every 2 weeks for at least 1 year prior to drug withdrawal. Each condition (drug or placebo) lasted 12 weeks. Using a radioimmunoassay verified by comparison to a gas chromatographic-mass spectrometric method, plasma fluphenazine levels were measured every 2 weeks during drug continuation and drug withdrawal conditions. No patient relapsed over the 24-week period of the study. Mean fluphenazine levels between drug continuation and withdrawal conditions showed a progressively larger difference over time, although significant differences were not seen until week 8. By week 12 after drug withdrawal, 33% of subjects still showed notable plasma fluphenazine levels. On the basis of our preliminary findings, we suggest that 2-week intervals between injections may be too short and that wider intervals may achieve similar clinical results.

Avoidant personality disorder symptoms in first-degree relatives of schizophrenia patients predict performance on neurocognitive measures: The UCLA family study

Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia. 367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models. Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3-7 Continuous Performance Test (3-7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent. Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype.

Fluphenazine levels during maintenance treatment of recent-onset schizophrenia: relation to side effects, psychosocial function and depression.

Abstract Rationale: The utility of fluphenazine levels during maintenance treatment of schizophrenia is still unclear. Objectives: This study investigated the relationship between fluphenazine levels and a variety of clinical measures during maintenance treatment of schizophrenia. Methods: Fluphenazine levels, side effects, depression and psychosocial outcome were measured at five time points over approximately 1 year in 59 recent onset schizophrenic patients treated with a maintenance dose of injectable fluphenazine decanoate. Negative symptoms were evaluated at the 1-year endpoint. Results: Fluphenazine levels showed marked intraindividual variability even when measurements were restricted to the second 6 months of treatment, by which time steady state levels should have been achieved. No consistent relationship was found between fluphenazine levels and any of the outcome measures. Conclusions: The results of this study suggest that fluphenazine plasma levels do not routinely add relevant clinical information beyond that of dose in evaluating potential side effects or negative consequences during maintenance treatment with the decanoate form of the medication.

Defining Treatment-Resistant Depression

Defining Treatment-Resistant Depression To the Editor In their Viewpoint, Conway et al1 noted the disparity in defining treatment-resistant depression (TRD) and sought to address the question: When does major depressive disorder become resistant? They believe TRD should be defined by lack of response to specific numbers of adequate doseduration trials of different established pharmacotherapy or psychotherapy classes. The authors argue the number of failed treatments constitutes an “inflection point” that predicts poor prognosis for efficacy, relapse, and tolerance of future treatments. They believe this will facilitate and accelerate the development of treatments for TRD by standardizing the definition of TRD. While we agree with the authors’ basic approach based on operationalizing the number of failed treatment attempts, we suggest that their approach could be refined in certain ways. First, the requirement that treatments be of different drug classes is not well supported. The Sequenced Treatment Alternatives to Relieve Depression Trial and other studies have shown that treatment outcome is significantly enhanced by a greater number of total trials and not by the use of drugs from different classes.2 Second, it is important to recognize that remission is a multifactorial concept. For example, it is possible for primary mood symptoms to resolve while significant cognitive dysfunctions (particularly executive dysfunction) remain,3 and these patients may require more specialized treatment interventions. Third, in operationalizing the selection of subsequent treatments, it may be important to consider differential responses to psychotherapy or medication treatment in those with a history of childhood adversity4 or comorbid personality disorder. Patients with such phenotypes may be at greater risk for resistance with particular treatments and in need of more aggressive combination approaches. Intermediate phenotypes with differential responses to treatment also may be identified by further subtyping using imaging, neurophysiologic, hormonal, and cellular and molecular measures.5 What is treatment resistant will not be the same in all studies. Defining TRD by poor treatment outcome with different drug classes perpetuates use of a neurochemical approach to TRD that may not be related to the fundamental mechanisms of the illness and is only a part of understanding TRD. Our research must do a better job of characterizing the heterogeneity of TRD by subtyping depression using clinical variables and physiological measures. Only then will we be able to realize the hopes of Conway et al1 of creating studies that might be combined to increase our power to understand and advance the treatment of TRD.

Temporal lobe thickness and verbal memory in first-degree relatives of individuals with schizophrenia

Cortical thinning in frontal and temporal regions has been reported in individuals diagnosed with schizophrenia and, less consistently, among their unaffected first-degree relatives. Likewise, first-degree relatives demonstrate attenuated differences in neurocognitive performance relative to healthy controls, indicating that neurocognitive performance may be an important endophenotype of the disorder. Less is known about how cortical thickness relates to neurocognitive performance in these individuals. Given the robust nature of temporal structural abnormalities in schizophrenia, this study aimed to identify how temporal lobe cortical thickness might relate to verbal memory in first-degree relatives. Unaffected parents and siblings of individuals with adult-onset schizophrenia (N=62) and individuals in healthy control families (N=70) participating in the UCLA Family Study received a structural MRI and completed a battery of neurocognitive tests. Cortical thickness was estimated across the cortex and thickness measures of all regions in the temporal lobe were summed, averaged, and residualized for age and sex to produce a variable. A verbal learning factor was derived from two common tests of verbal learning and memory, the CVLT-II and Logical Memory of the WMS-III. Results demonstrated a significant interaction between group and verbal learning in relationship to temporal lobe thickness. Post-hoc analyses revealed significant correlations between verbal learning and cortical thickness in the relatives of schizophrenia patients which were driven by immediate recall scores on the CVLT-II and Logical Memory. These findings indicate that cortical thickness in the temporal cortex may represent a structural correlate for encoding verbal information in unaffected relatives of individuals with schizophrenia.