Philip A. Cola

A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

Marked Elevations of Serum Creatine Kinase Activity Associated with Antipsychotic Drug Treatment

Serum creatine kinase (SCK) activity of the skeletal muscle (MM) form is sometimes moderately increased in acutely psychotic patients and may be massively increased as a result of muscle damage. The objective of this study was to characterize the SCK increases in patients treated with novel antipsychotic drugs. SCK activity and myoglobinuria, an index of gross muscle damage, were monitored at varying intervals in schizophrenic or schizoaffective patients treated with antipsychotic drugs. Possible causes of increases in SCK activity, such as trauma, excessive physical activity, exacerbation of psychosis, were assessed. Fifteen instances of massive increases in SCK activity were observed in 11 out of 121 patients (10%) treated with the following antipsychotic drugs: clozapine, loxapine, haloperidol, melperone, risperidone, or olanzapine. These increases in SCK activity were of the MM type and ranged from 1,206 to 177,363 IU/L (median, 9,600 IU/L). Thus, they were much larger than the increases usually found in acutely psychotic patients or patients with neuroleptic malignant syndrome (range, 500-3,000 IU/L). Only the patient with SCK activity of 177,363 IU/L had rhabdomyolysis as evidenced by myoglobinuria. The onset of the increases was from 5 days to 2 years after initiating treatment, and the increases lasted 4 to 28 days (median, 8 days). Flulike symptoms were present in two of the patients, but the others were asymptomatic. The increases were self-limiting in three cases, despite continuing treatment. Two of three cases rechallenged with the same drug again developed large increases in SCK activity within a week. It is unlikely these increases in SCK activity are related to acute psychosis, trauma, or the neuroleptic malignant syndrome. The increase in SCK activity may reflect the ability of the drugs to increase intermittently cell membrane permeability, especially in skeletal muscle, in some vulnerable subjects. A possible role of serotonin in this process is suggested by the pharmacology of most of the offending drugs. However, in some instances, the increases may have been unrelated to drug treatment. There was no evidence that these increases in SCK activity, despite their magnitude, compromised renal function. Routine monitoring of SCK activity of myoglobinuria during treatment with the antipsychotic drugs studied here is probably not necessary.

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients withneuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Plasma clozapine and desmethylclozapine levels in clozapine-induced agranulocytosis

Clozapine may produce agranulocytosis in 1–2% of patients treated with it for 4 weeks or longer. Three mechanisms have been suggested: a direct toxic effect of metabolite of clozapine, an immunologic mechanism or a combination of both. N-desmethylclozapine, the major metabolite of clozapine, has been reported to be more toxic than clozapine itself (Gerson et al., 1994). In this study, plasma levels of clozapine and desmethylclozapine were measured in five patients who developed agranulocytosis. The levels of both parent compound and metabolite were within the range found in other patients and below the toxic range. If a toxic mechanism is involved in clozapine-induced agranulocytosis, an additional vulnerability factor must be important.

A randomized trial comparing clozapine and typical neuroleptic drugs in non-treatment-resistant schizophrenia

Clozapine has been shown to be superior to typical neuroleptic drugs for treating positive symptoms in treatment-resistant (TR) schizophrenia. Long-term data from randomized clinical trials comparing clozapine with typical neuroleptics in non-TR schizophrenia are rare. We previously reported that clozapine was superior to typical neuroleptic drugs in some domains of cognition in recent onset non-TR schizophrenia. We now present data on psychopathology and quality of life from this randomized, flexibly dosed, 24-month study of clozapine vs. typical neuroleptics in non-TR schizophrenia patients. Both treatments produced significant improvement in measures of psychopathology, quality of life, and global function, with minor exceptions. There was no difference in extrapyramidal side effects between the patients treated with clozapine or typical neuroleptics. However, significantly more relapse/rehospitalization drop-outs occurred in the typical neuroleptic group. Two patients treated with typical neuroleptics, but none treated with clozapine, became non-responsive to treatment. Clozapine was associated with significantly greater weight gain. Clozapine and typical neuroleptic drugs appear to produce equivalent improvement in psychopathology in patients with non-TR schizophrenia. Clozapine may be more effective than typical neuroleptics for treatment retention and prevention of relapse, but it produces more severe metabolic side effects. These considerations should be taken into account in decisions of how best to utilize clozapine in the treatment of schizophrenia.

the Evolution of Treatment Resistance: Biologic Implications

&NA; The evolution of resistance of positive symptoms to antipsychotic therapy may represent a valuable means of subtyping schizophrenia. In contrast, resistance of negative symptoms and cognitive function to antipsychotic agents seems to be present from the first episode of psychotic symptoms and does not evolve over time to the same extent. If these findings are validated, this clearly points toward differences in the etiology of these components of schizophrenia. Data from a cohort of 223 patients with unsatisfactory responses to classical antipsychotic therapy are evaluated, at least 60% of whom responded to subsequent treatment with clozapine. Comparisons were made between the subgroups of patients with primary and delayed onset treatment resistance. Both subgroups responded to clozapine therapy, although better response was evident for patients with delayed resistance. The withdrawal of clozapine from patients who had previously been responsive to classical antipsychotic therapy was capable of inducing treatment resistance.

Research Participant-Centered Outcomes at NIH-Supported Clinical Research Centers

Although research participation is essential for clinical investigation, few quantitative outcome measures exist to assess participants’ experiences. To address this, we developed and deployed a survey at 15 NIH‐supported clinical research centers to assess participant‐centered outcomes; we report responses from 4,961 participants.

Empirical Assessment of Methodology in the History-of-Psychology Literature, 1975-1986

Psychological Abstracts was used to identify 1,161 history-of-psychology publications that appeared between 1975 and 1986. Information was obtained from each publication on the type of history (biographical, institutional, etc.), its historiography, the historical period that had been studied, and the quantitativeness of results. We found that the literature was mostly presentist in style and that the nineteenth and twentieth centuries received the bulk of attention. Publications that adopted an internalist perspective greatly outnumbered those with an externalist perspective. Quantitative methods were infrequently used. Results are discussed in reference to historiographic recommendations that had accompanied the institutionalization of the history of psychology in the late 1960s

Contributions to Psychohistory: XX. Ethnocentricity in the Recent History-Of-Psychology Literature

Literature in the history of psychology that had been published from 1975 through 1986 was identified in Psychological Abstracts (1975–1988). From each of the 1478 publications information was obtained on the historical setting of the narrative and the geographical location of the (first) author. Austria, Germany, and the United States were the most often chosen settings, and these three accounted for 43% of the settings chosen. Scholars in Mexico, Japan, and the USSR were the most likely to choose their own country as the historical setting (i.e., “ethnocentric”), and those in Canada were the least ethnocentric.

A Novel Protocol for Streamlined IRB Review of Practice-based Research Network (PBRN) Card Studies

Purpose: The “card study,” in which clinicians record brief information about patient visits during usual clinical care, has long been a rapid method for conducting descriptive studies in practice-based research networks. Because an increasingly stringent regulatory environment has made conducting card studies difficult, we developed a streamlined method for obtaining card study institutional review board (IRB) approval. Methods: We developed a protocol for a study of the card study method, allowing new card study proposals of specific research questions to be submitted as addenda to the approved Card Study Protocol. Results: Seven card studies were proposed and approved under the Card Study Protocol during the first year after implementation, contrasted with one-card study proposed in the previous year. New card study ideas submitted as addenda to an approved protocol appeared to increase IRB comfort with the card study as a minimal risk method while reducing the hurdles to developing new study ideas. Conclusions: A Card Study Protocol allowing new study questions to be submitted as addenda decreases time between idea generation and IRB approval. Shortened turn-around times may be useful for translating ideas into action while reducing regulatory burden.