Jimmy Lee

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Antipsychotics and Amotivation

Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation.

Extrapyramidal symptoms and cognitive test performance in patients with schizophrenia.

BACKGROUND Movement disorders are common in individuals with schizophrenia, even in those who are not exposed to antipsychotic medications. Extrapyramidal symptoms (EPS) are among the most common abnormal movements in schizophrenia, but their relationship with other features of the illness such as cognition is not well characterized. METHODS Three hundred and twenty-five individuals with schizophrenia who were not receiving any antipsychotic or anticholinergic medication and participated in the baseline visit of the Clinical Antipsychotic Treatment of Intervention Effectiveness study were included in the present study. EPSs were assessed using the Simpson-Angus Scale, while cognition was measured with a comprehensive neuropsychological test battery. The relationship between EPS and cognitive test performance was evaluated both dimensionally and categorically. RESULTS Greater severity of EPS was significantly associated with worse cognitive test performance evaluated using a composite score. Eighty-six patients were identified as having parkinsonism and these patients performed worse on cognitive tests than non-parkinsonian patients. These findings remained significant even after accounting for other variables such as severity of psychopathology, sedation, akathisia and dyskinesia. CONCLUSIONS The present results demonstrate that severity of EPS is reliably linked with poorer scores on tests of cognition. While this may reflect a common pathophysiology underlying neuromotor and neurocognitive deficits, it may also be the case that parkinsonian symptoms such as rigidity and bradykinesia impede test taking ability. Regardless of mechanism, inferences regarding cognitive impairment should take into account the presence of EPS, as well as other variables that may mediate cognitive test findings.

Prolonged deprivation of sleep-like rest raises metabolic rate in the Pacific beetle cockroach, Diploptera punctata (Eschscholtz)

SUMMARY Rats respond to sustained sleep deprivation with increased mortality preceded by a rise in resting metabolic rate that may or may not be attributed to dysfunction of the thermoregulatory system. The present study was designed to test the hypothesis that deprivation of sleep-like rest will lead to increased metabolic rate in an ectothermic insect, the Pacific beetle cockroach. A mild alerting stimulus consisting of a brief <1% pulse of CO2 and simultaneous 2 s rotation (1 cm motion) of the animal chamber consistently prevented the adoption of a sleep-like resting posture in cockroaches. Two groups of 15 male adult cockroaches were studied; a group targeted for deprivation of sleep-like rest (SD) was presented with one stimulus per minute continuously, and a group of stimulus controls (SC) was given the same number of stimuli per day but scheduled such that the animals received a 3 h interval without stimuli four times per day. This protocol led to significantly increased mortality in the SD group beginning on day 17 (averaging 0.57 deaths per day thereafter), but not in the SC group (averaging 0.17 deaths per day throughout). Oxygen consumption (V̇O2) increased significantly after 4 weeks in the SD group but not the SC group. V̇O2 was 82% above pre-deprivation baseline after 35 days in the SD group (P=0.009). Body mass was unchanged throughout. We conclude that sleep-like rest is essential for long-term viability in insects and that prolonged vigilance leads to an increase in whole-animal metabolic rate in this ectothermic species.

The Effect of Clozapine on Hematological Indices: A 1-Year Follow-Up Study.

Abstract Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and is linked to a need for mandatory hematological monitoring. Besides agranulocytosis, other hematological aberrations have resulted in premature termination in some cases. Considering clozapines role in immunomodulation, we proceeded to investigate the impact of clozapine on the following 3 main hematological cell lines: red blood cells, platelets, white blood cells (WBCs), and its differential counts. Data were extracted from patients initiated on clozapine between January 2009 and December 2010 at a single hospital. Patients with a preclozapine complete blood count, who were receiving clozapine during the 1-year follow-up period, were included in the present investigation. Counts of red blood cells, platelets, WBC, and its differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils were extracted and trajectories plotted. One hundred one patients were included in this study and 66 remained on clozapine at the end of 1 year. There was a synchronized but transient increase in WBC, neutrophils, monocytes, eosinophils, basophils, and platelets beginning as early as the first week of clozapine treatment. There were no cases of agranulocytosis reported in this sample, and five developed neutropenia. A spike in neutrophils immediately preceded the onset of neutropenia in three of the five. The cumulative incidence rates were 48.9% for neutrophilia, 5.9% for eosinophilia, and 3% each for thrombocytosis and thrombocytopenia. Early hematological aberrations are visible across a range of cell lines, primarily of the myeloid lineage. These disturbances are transient and are probably related to clozapines immunomodulatory properties. We do not suggest discontinuing clozapine as a consequence of the observed aberrations.

Determinants of patient-rated and clinician-rated illness severity in schizophrenia

OBJECTIVE The contribution of specific symptoms on ratings of global illness severity in patients with schizophrenia is not well understood. The present study examined the clinical determinants of clinician and patient ratings of overall illness severity. METHOD This study included 1,010 patients with a DSM-IV diagnosis of schizophrenia who participated in the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study conducted between January 2001 and December 2004 and who had available symptom severity, side effect burden, cognition, and community functioning data. Both clinicians and patients completed the 7-point Clinical Global Impressions-Severity of Illness scale (CGI-S), the primary measure of interest in the present study. Symptoms were rated using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia, and functional status with the Quality of Life Scale. Neurocognition, insight, and medication-related side effects were also evaluated. RESULTS Clinicians rated illness severity significantly higher than patients (P < .001). There was moderate overlap between CGI-S ratings made by clinicians and patients, with almost one third of patients showing substantial (ie, greater than 1 point) discrepancies with clinician ratings. Clinician-rated CGI-S scores were most strongly associated with positive symptoms, with additional independent contributions made by negative, disorganized, and depressive symptoms, as well as functional outcome (all P values < .01). Patient-rated CGI-S scores, on the other hand, were most closely related to depressive symptoms, with additional independent contributions made by positive and anxiety symptoms, clinical insight, and neurocognition (all P values < .01). Depressive symptoms were the strongest predictor of patient-rated CGI-S scores even in patients with good clinical insight (P < .001). CONCLUSIONS Patient and clinician views of overall illness severity are not necessarily interchangeable and differ in their clinical correlates. Taking these differences into account may enhance patient engagement in care and improve outcomes. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00014001.

Clinical and functional outcomes in people with schizophrenia with a high sense of well-being

Abstract Optimal outcome in schizophrenia is thought to include remission of symptoms, functional recovery, and improved subjective well-being. The present study examined the characteristics of individuals with schizophrenia who report being satisfied with their life in general. Individuals with schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness study were included in the present analysis. Approximately half of the individuals evaluated reported a high level of life satisfaction, even while many concurrently described themselves as at least moderately ill and experiencing moderate-severe symptoms and manifested severe functional deficits. Of all individuals evaluated, only about 1% experienced what was considered to be optimal outcome. Individuals with schizophrenia are able to experience a high level of life satisfaction, despite experiencing severe illness and functional deficits. Those involved in care should be aware that life satisfaction as an outcome is not necessarily associated with symptom remission and superior functioning.

Relationship between symptomatic improvement and overall illness severity in patients with schizophrenia.

Background Whether improvement on ratings of global illness severity is differentially associated with improvement in specific symptom domains in patients with schizophrenia is not well understood. The present study examined the independent relationships between improvement in specific symptom clusters and change in global impressions of illness severity. Methods This study included 589 patients with chronic schizophrenia who were assessed at baseline and after 6 months of antipsychotic treatment. Both clinicians and patients completed the Clinical Global Impressions–Severity of Illness Scale (CGI-S). Symptom severity was assessed using factor scores derived from the Positive and Negative Syndrome Scale. Results Change in illness severity ratings made by the clinician and those made by the patient demonstrated moderate overlap. Nearly half of the patients were evaluated as clinically improved during the 6-month period, as rated by the clinician, with less than a third of patients experiencing a reduction in illness severity as determined by both the clinician and themselves. Improvements in clinician-rated CGI-S scores were most strongly associated with reduction in positive symptom severity. In contrast, change in patient-rated CGI-S scores was not linked to reduction in positive symptoms but rather to improvement in depressive and anxiety symptoms. This latter finding remained in a subsample of patients with relatively preserved insight into illness, suggesting that lack of insight cannot account for these findings. Finally, reduction in positive symptoms beyond 2 to 3 points was found to be clinically meaningful. Conclusions In conclusion, change in overall illness severity, as determined by clinicians, is not necessarily interchangeable with patients’ view of improvement of their own clinical status. Moreover, changes in the 2 evaluations of illness severity are associated with changes in different symptom domains.

Clozapine and Anemia: A 2-Year Follow-Up Study

OBJECTIVE Clozapines association with agranulocytosis led to the implementation of stringent and mandatory hematologic monitoring guidelines in most countries. Although other hematologic aberrations such as eosinophilia and neutropenia have been previously described, clozapines impact on the erythroid lineage has not been studied. There is a suspicion that a higher rate of anemia is observed in patients receiving clozapine; therefore, we hypothesized that there would be a higher rate of anemia in patients receiving clozapine therapy. METHOD All individuals initiated on clozapine at our center from 2009 to 2010 were recruited. Information on age, gender, medical comorbidities, and smoking status was extracted from the medical records. Data from complete blood counts over a 2-year follow-up period were extracted, with anemia defined as a hemoglobin value below 120 g/L for women and 130 g/L for men. Time to anemia event was calculated and Cox regression was employed to identify predictors of anemia. RESULTS We found a high incidence of anemia in the first 2 years following clozapine initiation; of the 94 individuals (68 men, 26 women) recruited, 23 (24.5%) developed anemia. Higher baseline hemoglobin level (hazard ratio [HR] = 0.86, P = .002) and smoking status (HR = 0.21, P = .021) were identified as significant protective factors against anemia in men but not in women (HR = 0.92, P = .184, and HR = 0.52, P = .467 for baseline hemoglobin and smoking, respectively). CONCLUSIONS Although smoking appears to lower the risk of anemia, we believe this is due to smokings up-regulation of hemoglobin levels. Further studies are warranted in light of the present findings; for example, we cannot exclude the possibility that anemia was an epiphenomenon, characterizing instead a population with severe mental illness.

AutoPap 300 QC System Scoring of Cervical Smears Without “Epithelial Cell Abnormalities”

OBJECTIVE To examine four morphologic features other than epithelial abnormality to identify if they are associated with a high quality control (QC) score with the AutoPap 300 QC system. STUDY DESIGN A total of 180 slides (140 with a high QC score and 40 with a low QC score [the control group]) were manually reviewed, and four morphologic features were assessed while blind to the QC score, as follows: adequacy, epithelial fragments and clumps, cytohormonal pattern, and diagnostic categories within normal limits and benign cellular changes (BCC). RESULTS Both atrophy and a diagnosis of BCC were associated with a high QC score at a statistically significant level. CONCLUSION Certain characteristics of the slide population submitted for AutoPap QC review could have an impact on the overall laboratory workload (QC review rate). There are opportunities to optimize the workload of the laboratory when using AutoPap for QC selection.