Lawrence Adler

Baseline neurocognitive deficits in the CATIE schizophrenia trial

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An ‘all-comer’ approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13–0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an ‘all-comer’ clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Olanzapine reduces craving for alcohol: a DRD4 VNTR polymorphism by pharmacotherapy interaction.

Separate investigations have suggested that olanzapine, a D4 antagonist, decreases craving after a priming dose of alcohol and that the DRD4 variable number of tandem repeats (VNTR) polymorphism influences the expression of craving after a priming dose of alcohol. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers. Participants were randomly assigned to receive olanzapine (5 mg) or a control medication (cyproheptadine, 4 mg) prior to consuming three alcoholic drinks. Participants completed subjective measures of craving and euphoria after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele of the DRD4 VNTR were classified as DRD4 L, while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals.

Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy

OBJECTIVE This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Schizophrenia: age at onset, gender and familial risk

In a family history study of 366 schizophrenic probands and their 1851 first‐degree relatives, we found a relationship between age at onset of psychosis in the male probands and the risk for schizophrenia in their relatives. The relatives of male schizophrenic probands whose onset of psychosis occurred when they were younger than 17 years of age had an increased risk of schizophrenia when compared with the relatives of male probands with an age at onset greater than 17. We did not find an association between age at onset of psychosis in the female probands and familial risk. Cox proportional hazards models permitted us to examine the relationship between age at onset of psychosis in the probands and familial risk while controlling for possible confounding effects.

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

OBJECTIVE The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

Obsessive-compulsive symptoms in schizophrenia

In order to improve the outcome of schizophrenia, we must deepen our understanding of its heterogeneous aspect. At the same time, we must search for homogeneous subtypes characterized by consistent clinical aspects so that we may develop specific and more effective treatments. Researchers have long categorized schizophrenia as a syndrome manifested through a number of distinct subtypes that share the same morbid process but have sufficient differences to warrant distinct subtyping (Berman et al., 1995a; Fenton and McGlashan, 1986; Rosen, 1957; Stengel, 1945). Using genetic, neurological, biochemical and outcome markers, research continues to focus on the search for homogeneous subtypes (Goldstein and Tsuang, 1988).

Valproate-Related Hyperammonemia in Older Adult Psychiatric Inpatients.

To the Editor: Valproate is indicated for treatment of seizure disorders and mania in bipolar disorder and is prescribed off-label to treat impulsivity, aggression, irritability, and agitation in other disorders. Prescribing information for valproate includes warnings for hyperammonemic encephalopathy in individuals with urea cycle disorders and for hyperammonemia despite normal liver function tests. A cohort study of 123 valproate-treated psychiatric inpatients (mean age of 45.1 years) reported a valproate-related hyperammonemia rate of 51.2%.1 Neuropsychiatric manifestations of valproate-related hyperammonemia can include lethargy, tremor, ataxia, and mental status changes, although patients may be asymptomatic.1–3 In older adult patients, age-related metabolic changes and greater vulnerability of the aged brain may increase risk for mental status changes. Published literature on valproate-related hyperammonemia in older adults is limited to case reports without comparison to patients not taking valproate.4 This study aimed to ascertain the clinical significance of valproate-related hyperammonemia in older adult psychiatric inpatients by determining (1) whether, in the absence of liver disease, valproate-related hyperammonemia is more frequent in older adult psychiatric inpatients taking valproate compared to those not taking valproate and (2) the frequency of clinically significant adverse effects of valproate-related hyperammonemia in older adult psychiatric inpatients. Method. This retrospective chart review study, approved by the University of Maryland Institutional Review Board, examined the medical records of all admissions to the Older Adult Psychiatric Inpatient Unit at the University of Maryland Medical Center, Baltimore, Maryland, from October 2007 to April 2010. A total of 235 patients met the following inclusion criteria: (1) age ≥ 50 years, (2) available routine admission screening levels of ammonia, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), (3) AST and ALT levels less than twice the upper normal limits, and (4) no history of active liver disease. Hyperammonemia was defined as a plasma ammonia level ≥ 35 μmol/L.5 Patients were grouped by valproate status at admission. Continuous variables were analyzed by Mann-Whitney U test for grouped analyses and Spearman ρ for correlations. Categorical variables were analyzed by χ2 tests with continuity correction for 2 group analyses. Analysis by race was limited to the 2 most populated categories. All tests were 2-tailed with statistical significance set as P ≤ .05 and performed using SPSS 21.0 (SPSS Inc, Chicago, Illinois). Results. Median ammonia level and rate of hyperammonemia in patients taking valproate at admission were significantly greater than in patients not taking valproate at admission (Table 1). Otherwise, there were no significant differences between groups on variables assessed. In patients taking valproate, ammonia level correlated significantly with valproate dose (ρ = 0.337, n = 37, P = .042), but not with serum levels of valproate (ρ = −0.015, n = 26, P = .940), AST (ρ = 0.059, P = .718), or ALT (ρ = 0.181, P = .264). Diagnoses (DSM-IV) of the 40 patients taking valproate were mood disorders (n = 18), schizoaffective disorder (n = 10), schizophrenia (n = 6), and dementia with behavioral disturbance (n = 6). The 29 patients with valproate-related hyperammonemia were compared to the 11 patients taking valproate without hyperammonemia; the only variable demonstrating significant difference was valproate dose (U = 81, P = .033). Patients with hyperammonemia had a higher median valproate daily dose of 1,000 mg compared to 750 mg in patients without hyperammonemia. Three of 29 patients with valproate-related hyperammonemia (mean ammonia level of 74 μmol/L) had clinically significant adverse effects—cognitive impairment in all 3 and tremors in one. Table 1 Older Adult Psychiatric Inpatients Grouped by Valproate Use To our knowledge, this is the first study to examine the frequency of hyperammonemia in a sample of older adults taking valproate compared to those not taking valproate. Valproate use increased risk for hyperammonemia 2-fold (relative risk = 2.18, confidence interval = 1.65–2.86). Clinically significant adverse effects occurred in approximately 10% of patients with valproate-related hyperammonemia at ammonia levels around twice the upper normal limit. Clinicians should obtain ammonia levels when mental status changes arise in older adults taking valproate.

Elevated Plasma Aβ42 in Cognitively Impaired Individuals Taking ACE Inhibitor Antihypertensives

Background/Rationale: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-β (Aβ), possibly indicating improved Aβ clearance from brain to blood. Methods: We measured and compared plasma concentrations of Aβ42, Aβ40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer’s disease (AD) dementia, and mixed probable AD/vascular dementia. Results: Plasma Aβ42 levels and Aβ42/Aβ40 ratios of participants taking ACE-Is (n = 11) significantly exceeded (t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). Conclusions: This study is the first to show an association between ACE-I use and increased plasma Aβ42 level and Aβ42/Aβ40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aβ42 indicates improved Aβ42 clearance from brain that contributes to protection from cognitive decline.

Learning and recall inefficiency in schizophrenia

Schizophrenic patients have demonstrated deficits on measures of attention, learning, and working memory. It has also been suggested that the semantic network may be compromised in these individuals. We sought to examine aspects of memory function in this population using the Cahfornia Verbal Learning Test (CVLT). Thirty two schizophrenic and 32 normal individuals of similar age and education were compared on indices of learning, memory, and semantic organization. In addition, types of false positive errors on a recognition trial were analyzed . Schizophrenics performed more poorly than controls on indices of free recall, retention, and semantic clustering but performed similarly t~ contro~s on cued recall and ~~rd recognition trials. SchlZophremcs made more false positive errors on words which were semantically related to target words but were not different from normals on phonemic or other false positive errors. Deficits may reflect a disrupt ion in the semantic network or an executive function deficit which interferes with strategic learning and recall efforts. These results are consistent with findings of inefficient learning as well as working memory deficitspreviously reported in this population.