Clifford M. Cassidy

Testing Definitions of Symptom Remission in First-Episode Psychosis for Prediction of Functional Outcome at 2 Years

BACKGROUND To determine the clinical relevance of different definitions of symptom remission for prediction of functional outcome in first-episode psychosis (FEP). METHODS One hundred forty-one individuals receiving treatment for an FEP at a specialized early intervention service had positive and negative symptoms and functional status rated every month over the first 2 years of treatment using the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Subjects were classified according to 4 definitions of remission varying the criteria for severity (negative symptom inclusion/exclusion) and duration (3/6 mo sustained). RESULTS Positive symptom remission was achieved by 94% and 84% of subjects for 3 and 6 months, respectively, compared with 70% and 56% for positive and negative symptom remission, respectively. Linear regression analyses showed that only definitions of remission containing both positive and negative symptoms independently predicted functional outcome. This was confirmed by receiver operating characteristic analyses where remission based on positive and negative symptoms was marginally better than positive symptoms alone (difference in area under the curve; z = 1.94, P = .052). There was little difference between a time criterion of remission of positive and negative symptoms of 3 (sensitivity = 100%, specificity = 42%) or 6 (sensitivity = 90%, specificity = 57%) months. DISCUSSION Consistent with the consensus definition of remission in schizophrenia, severity of both positive and negative symptoms in defining remission in FEP is necessary although a 3-month criterion had equal predictive validity to the 6-month criterion.

Factors influencing relapse during a 2-year follow-up of first-episode psychosis in a specialized early intervention service.

BACKGROUND Differential association of risk factors associated with relapse following treatment of first-episode psychosis (FEP) have not been studied adequately, especially for patients treated in specialized early intervention (SEI) services, where some of the usual risk factors may be ameliorated. METHOD Consecutive FEP patients treated in an SEI service over a 4-year period were evaluated for relapse during a 2-year follow-up. Relapse was based on ratings on the Scale for Assessment of Positive Symptoms (SAPS) and weekly ratings based on the Life Chart Schedule (LCS). Predictor variables included gender, duration of untreated psychosis (DUP), total duration of untreated illness (DUI), age of onset, pre-morbid adjustment, co-morbid diagnosis of substance abuse during follow-up and adherence to medication. Univariate analyses were followed by logistic regression for rate of relapse and survival analysis with the Cox proportional-hazards regression model for time to relapse as the dependent variables. RESULTS Of the 189 eligible patients, 145 achieved remission of positive symptoms. A high rate of medication adherence (85%) and relatively low relapse rates (29.7%) were observed over the 2-year follow-up. A higher relapse rate was associated with a co-morbid diagnosis of substance abuse assessed during the follow-up period [odds ratio (OR) 2.84, 95% confidence interval (CI) 1.24-6.51]. The length of time to relapse was not associated with any single predictor. CONCLUSIONS Specialized treatment of substance abuse may be necessary to further reduce risk of relapse even after improving adherence to medication.

A comparison study of multiple measures of adherence to antipsychotic medication in first-episode psychosis.

Abstract This study evaluates how much agreement there is between subjective reports of adherence to antipsychotic medication and objective or derived measures of adherence in first-episode psychosis (FEP) and asks if any adherence measure could approximate a gold standard based on correlation to symptom improvement in the early phase of treatment. Adherence was assessed in 81 FEP subjects on a monthly basis by reports from patients, clinicians, family, and pill counting. A consensus measure of adherence was derived from all available sources of adherence data. Symptoms were measured using the Positive and Negative Syndrome Scale at study entry and 3 months subsequently. Adherence as measured by patient report, pill count, and clinician report were in good agreement with each other (intraclass correlation coefficient = 0.84), and all of these measures were highly correlated to consensus adherence (r values between 0.86 and 0.98). Mean adherence was slightly higher as rated by patients (83% full doses taken per month) and family members (91%) than by clinicians (76%), pill counting (73%), or consensus value (74%). Early in treatment, each measure of adherence (except family report) was significantly associated with positive symptom reduction, although the order of magnitude of this correlation was greater for pill count and consensus adherence (P < 0.01) compared with patient- or clinician-reported adherence (P < 0.05). Patient or clinician reports provide a reasonable estimate of medication adherence in FEP, but introducing pill counting or a derived measure of adherence may allow more accurate measurement.

Validation of the alcohol use disorders identification test and the drug abuse screening test in first episode psychosis.

Objective: To determine the validity and reliability of the Alcohol Use Disorders Identification Test (AUDIT) and Drug Abuse Screening Test (DAST) for detecting alcohol and drug use disorders, respectively, in a population with first-episode psychosis (FEP). Method: Subjects with FEP completed the AUDIT and DAST and were divided into groups according to the presence or absence of a Structured Clinical Interview for DSM-IV (SCID) diagnosis of either current alcohol or drug misuse. The data were analyzed to see whether AUDIT and DAST scores were predictive of SCID diagnosis. Results: Patients with alcohol-related SCID diagnoses and those with drug-related SCID diagnoses scored significantly higher on the AUDIT and DAST, respectively, than the group without the respective SCID diagnosis (P < 0.001 in both cases). The AUDIT functioned best with a problem drinking cut-off score of 10 (sensitivity, 85%; specificity, 91%). The DAST functioned best with a problem drug use cut-off score of 3 (sensitivity, 85%; specificity, 73%). The area under the receiver operating characteristic curve was 0.86 for the AUDIT and 0.83 for the DAST. Conclusion: The DAST and AUDIT may reliably identify FEP patients with substance abuse.

Deficits in striatal dopamine release in cannabis dependence.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5–7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO-binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence—without the confounds of any comorbidity—is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.

Cannabis use and anticipatory pleasure as reported by subjects with early psychosis and community controls.

BACKGROUND There is evidence of decreased pleasure and deficits in the anticipation of reward in both psychotic illness and drug addiction. Individuals with low anticipatory pleasure may preferentially engage in behaviours associated with immediate reward such as cannabis use. METHOD Ninety-one psychosis patients and 91 controls without history of psychosis were administered the Temporal Experience of Pleasure Scale (TEPS), a self report which measures anticipatory and consummatory pleasure. Cannabis use diagnosis was assessed using the Structured Clinical Interview for DSM IV (SCID). Subjects reported the frequency of cannabis consumption and time since last use. RESULTS Patients did not show a significant deficit in anticipatory or consummatory pleasure compared to controls; however, patients with an active cannabis-use disorder tended to have lower consummatory pleasure than controls with active cannabis disorder (p<.05). Patients who continued to use cannabis during treatment of their first episode of psychosis reported significantly lower anticipatory pleasure compared to those who had a lifetime cannabis diagnosis but were able to maintain abstinence (F(1,60)=5.6, p=.021). Frequency of cannabis use was negatively correlated to anticipatory and consummatory pleasure (Pearson R=-.46, -.48 respectively) in 37 patients currently using cannabis but not in 46 cannabis-using controls (partial R=-.04, -.07 respectively). CONCLUSION Anticipatory pleasure may not be decreased in early psychosis patients. Lower hedonic response may be associated with persistent, heavy cannabis use in patients in the early phase of psychotic disorders.

Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during an n-back working-memory task) and positron emission tomography using the radiotracer [11C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity. SIGNIFICANCE STATEMENT It is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.

Long-term effects of a community intervention for early identification of first-episode psychosis.

Objective:  To assess whether an Early Case Identification Program (ECIP) for first‐episode psychosis (FEP), which showed no significant short‐term effects, has a delayed impact on duration of untreated psychosis (DUP).

The Influence of Perceived Social Support on Medication Adherence in First-Episode Psychosis:

Objective: Our study examines the unique influence of social and family support on adherence to medication in a sample of patients treated for first-episode psychosis (FEP). Method: Social and family support using the Multidimensional Scale of Perceived Social Support and medication adherence (consensus of subjective and objective data) were evaluated on a monthly basis during a 6-month period in a sample of 82 FEP patients. The relation between social support and adherence was evaluated using correlational and linear regression analyses, controlling for other relevant variables. A longitudinal analysis using hierarchical linear models was conducted to model change in adherence over time. Results: Monthly correlations between social support and adherence were significant at 4 of 7 time points during a 6-month period. There was a modest correlation between the percentage of months of good adherence and the average level of family support across the study period. The linear regression failed to demonstrate a significant relation between baseline social support and overall adherence during the entire study period. Change in social support over time was inversely associated with change in adherence. Conclusions: Our study emphasizes the concurrent influence of social (mostly family) support on adherence but this effect does not persist over time. Changes in the degree of social support may have a complex effect on changes in adherence.

Case manager- and patient-rated alliance as a predictor of medication adherence in first-episode psychosis.

Objective The objective of this study was to evaluate the association between adherence to antipsychotic medication and working alliance (WA) ratings as reported separately by case manager (CM) and patient in first-episode psychosis (FEP) and to identify whether other factors previously related to adherence influence this relationship. Methods Adherence was evaluated every month in 81 participants who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychotic disorder (affective or nonaffective) and were treated in a specialized early intervention program. Adherence was measured, taking into account information from patient and clinician reports and pill counting. The WA, as assessed by both CM and patient, was assessed using the Working Alliance Inventory. Results The WA was stable during the course of the study as rated by both patient and CM. The “task” domain of WA was the subdomain most significantly correlated to adherence in cross-sectional analysis. The WA as measured by CM at study baseline was a significant predictor of the number of subsequent months with “good” adherence independently of other variables, including adherence at treatment onset (&bgr; = 0.011; P = 0.020; 95% confidence interval, 0.002–0.020). However, the WA as measured by patients was not similarly predictive of subsequent adherence (&bgr; = 0.003; P = 0.31; 95% confidence interval, −0.003 to 0.010). Conclusions The CM-rated WA is a significant predictor of future medication adherence in FEP, suggesting that good alliance can improve adherence in this population.