Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Elucidating the relationship between white matter structure, demographic, and clinical variables in schizophrenia-a multicenter harmonized diffusion tensor imaging study.

White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) "Which clinical variables explain WM abnormalities?". (2) "Does the degree of WM abnormalities predict symptom severity?". (3) "Does sex influence any of those relationships?". Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships.

A comparison of neurocognition and functioning in first episode psychosis populations: do research samples reflect the real world?

PURPOSE: The current study evaluates the demographic, clinical, and neurocognitive characteristics of a recruited FEP research sample, a research control group, and a FEP clinic sample that were assessed and treated within the same center and time period. METHODS: This study utilized data collected through an observational study and a retrospective chart review. Samples were ascertained in the Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults study and the Prevention and Recovery in Early Psychosis clinic. FEP clinic patients (n = 77), FEP research participants (n = 44), and age-matched controls (n = 38) were assessed using the MATRICS consensus cognitive battery and global functioning social and role scales. Between-group differences were assessed via one-way ANOVA and Chi-square analyses. RESULTS: No significant differences were observed between groups with regard to age and gender. The FEP research sample had a higher proportion of white participants, better social and role functioning, and better neurocognitive performance when compared with the FEP clinical population. The clinic sample also had more diagnostic variability and higher prevalence of substance use disorders relative to the FEP research sample. CONCLUSIONS: Researchers should be aware of how study design and recruitment practices may impact the representativeness of samples, with particular concern for equal representation of racial minorities and patients with more severe illness. Studies should be designed to minimize burden to promote a wider range of participation.

Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia.

We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

A randomized trial of clozapine vs. other antipsychotics for cannabis use disorder in patients with schizophrenia.

OBJECTIVE: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. We launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. METHODS: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Follow-back for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time-varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. RESULTS: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = -1.77; df = 28.5; p=.086; effect size ~ 0.6). Symptoms and functioning were not different between the two groups. CONCLUSIONS: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted.

Abnormal Frequency Mismatch Negativity in Early Psychosis Outpatient Subjects.

Background. Abnormalities of mismatch negativity (MMN), an event-related potential, indexing preattentive mechanisms, are consistently reported in schizophrenia (SZ). MMN abnormalities elicited to different deviant types have been recently shown to distinguish among patients according to length of their illness as well as inpatient versus outpatient status, and to be modulated by premorbid IQ. The objective of this study was to evaluate the MMN elicited by both frequency and duration deviant stimuli in patients with early schizophrenia (EP) recruited from an outpatient clinic in Boston, Massachusetts. Methods. Twenty-two healthy controls (HC) and 22 age-, handedness-, and gender-matched EP were tested using a frequency and duration MMN paradigm. Clinical data were also collected. Results. Frequency MMN amplitude but not duration MMN was significantly reduced in EP relative to HC subjects (P = .015). Conclusions. These results indicate that in this sample of early psychosis outpatient group, reductions in frequency MMN but not in duration MMN index clinical status. The relationship between age at first hospitalization and MMN frequency and duration amplitude and latency indicates that neurodevelopmental stage, auditory function, and clinical status are tightly linked.

Cingulum bundle abnormalities and risk for schizophrenia.

BACKGROUND: The cingulum bundle (CB) is a major white matter fiber tract of the limbic system that underlies cingulate cortex, passing longitudinally over the corpus callosum. The connectivity of this white matter fiber tract plays a major role in emotional expression, attention, motivation, and working memory, all of which are affected in schizophrenia. Myelin related CB abnormalities have also been implicated in schizophrenia. The purpose of this study is to determine whether or not CB abnormalities are evident in individuals at clinical high risk (CHR) for psychosis, and whether or not cognitive deficits in the domains subserved by CB are related to its structural abnormalities. METHODS: Diffusion Tensor Imaging (DTI) was performed on a 3 T magnet. DT tractography was used to evaluate CB in 20 individuals meeting CHR criteria (13 males/7 females) and 23 healthy controls (12 males/11 females) group matched on age, gender, parental socioeconomic status, education, and handedness. Fractional anisotropy (FA), a measure of white matter coherence and integrity, radial diffusivity (RD), thought to reflect myelin integrity, trace, a possible marker of atrophy, and axial diffusivity (AD), thought to reflect axonal integrity, were averaged over the entire tract and used to investigate CB abnormalities in individuals at CHR for psychosis compared with healthy controls. RESULTS: Significant group differences were found between individuals at CHR for psychosis and controls for FA (p = 0.028), RD (p = 0.03) and trace (p = 0.031), but not for AD (p = 0.09). We did not find any significant correlations between DTI measures and clinical symptoms. CONCLUSION: These findings suggest abnormalities (possibly myelin related) in the CB in individuals at CHR for psychosis.

Diffusion abnormalities in the corpus callosum in first episode schizophrenia: Associated with enlarged lateral ventricles and symptomatology.

INTRODUCTION: Abnormalities in the corpus callosum (CC) and the lateral ventricles (LV) are hallmark features of schizophrenia. These abnormalities have been reported in chronic and in first episode schizophrenia (FESZ). Here we explore further associations between CC and LV in FESZ using diffusion tensor imaging (DTI). METHODS: . Sixteen FESZ patients and 16 healthy controls (HC), matched on age, gender, and handedness participated in the study. Diffusion and structural imaging scans were acquired on a 3T GE Signa magnet. Volumetric measures for LV and DTI measures for five CC subdivisions were completed in both groups. In addition, two-tensor tractography, the latter corrected for free-water (FAt), was completed for CC. Correlations between LV and DTI measures of the CC were examined in both groups, while correlations between DTI and clinical measures were examined in only FESZ. RESULTS: Results from two-tensor tractography demonstrated decreased FAt and increased trace and radial diffusivity (RDt) in the five CC subdivisions in FESZ compared to HC. Central CC diffusion measures in FESZ were significantly correlated with volume of the LV, i.e., decreased FAt values were associated with larger LV volume, while increased RDt and trace values were associated with larger LV volume. In controls, correlations were also significant, but they were in the opposite direction from FESZ. In addition, decreased FAt in FESZ was associated with more positive symptoms. DISCUSSION: Partial volume corrected FAt, RDt, and trace abnormalities in the CC in FESZ suggest possible de- or dys-myelination, or changes in axonal diameters, all compatible with neurodevelopmental theories of schizophrenia. Correlational findings between the volume of LV and diffusion measures in FESZ reinforce the concept of a link between abnormalities in the LV and CC in early stages of schizophrenia and are also compatible with neurodevelopmental abnormalities in this population.

Progressive reduction of auditory evoked gamma in first episode schizophrenia but not clinical high risk individuals.

The early auditory-evoked gamma band response (EAGBR) may serve as an index of the integrity of fast recurrent inhibition or synaptic connectivity in the auditory cortex, where abnormalities in individuals with schizophrenia have been consistently found. The EAGBR has been rarely investigated in first episode schizophrenia patients (FESZ) and individuals at clinical high risk (CHR) for schizophrenia, and never been compared directly between these populations nor evaluated longitudinally. Here we examined the EAGBR in FESZ, CHR, and matched healthy controls (HC) at baseline and 1-year follow-up assessments to determine whether the EAGBR was affected in these clinical groups, and whether any EAGBR abnormalities changed over time. The electroencephalogram was recorded with a dense electrode array while subjects (18 FESZ, 18 CHR, and 40 HC) performed an auditory oddball task. Event-related spectral measures (phase locking factor [PLF] and evoked power) were computed on Morlet-wavelet-transformed single epochs from the standard trials. At baseline, EAGBR PLF and evoked power did not differ between groups. FESZ showed progressive reductions of PLF and evoked power from baseline to follow-up, and deficits in PLF at follow-up compared to HC. EAGBR peak frequency also increased at temporal sites in FESZ from baseline to follow-up. Longitudinal effects on the EAGBR were not found in CHR or HC, nor did these groups differ at follow-up. In conclusion, we detected neurophysiological changes of auditory cortex function in FESZ during a one-year period, which were not observed in CHR. These findings are discussed within the context of neurodevelopmental models of schizophrenia.

Utilizing Mutual Information Analysis to Explore the Relationship Between Gray and White Matter Structural Pathologies in Schizophrenia.

Schizophrenia has been characterized as a neurodevelopmental disorder, with structural brain abnormalities reported at all stages. However, at present, it remains unclear whether gray and white matter abnormalities represent related or independent pathologies in schizophrenia. In this study, we present findings from an integrative analysis exploring the morphological relationship between gray and white matter in 45 schizophrenia participants and 49 healthy controls. We utilized mutual information (MI), a measure of how much information two variables share, to assess the morphological dependence between gray and white matter in three segments of the corpus callsoum, and the gray matter regions these segments connect: (1) the genu and the left and right rostral middle frontal gyrus (rMFG), (2) the isthmus and the left and right superior temporal gyrus (STG), (3) the splenium and the left and right lateral occipital gyrus (LOG). We report significantly reduced MI between white matter tract dispersion of the right hemispheric callosal connections to the STG and both cortical thickness and area in the right STG in schizophrenia patients, despite a lack of group differences in cortical thickness, surface area, or dispersion. We believe that this reduction in morphological dependence between gray and white matter may reflect a possible decoupling of the developmental processes that shape morphological features of white and gray matter early in life. The present study also demonstrates the importance of studying the relationship between gray and white matter measures, as opposed to restricting analyses to gray and white matter measures independently.

Alteration of gray matter microstructure in schizophrenia.

Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Tractography Analysis of 5 White Matter Bundles and Their Clinical and Cognitive Correlates in Early-Course Schizophrenia.

PURPOSE: Tractography is the most anatomically accurate method for delineating white matter tracts in the brain, yet few studies have examined multiple tracts using tractography in patients with schizophrenia (SCZ). We analyze 5 white matter connections important in the pathophysiology of SCZ: uncinate fasciculus, cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus, and arcuate fasciculus (AF). Additionally, we investigate the relationship between diffusion tensor imaging (DTI) markers and neuropsychological measures. METHODS: High-resolution DTI data were acquired on a 3 Tesla scanner in 30 patients with early-course SCZ and 30 healthy controls (HC) from the Boston Center for Intervention Development and Applied Research study. After manually guided tracts delineation, fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD) were calculated and averaged along each tract. The association of DTI measures with the Scales for the Assessment of Negative and Positive Symptoms and neuropsychological measures was evaluated. RESULTS: Compared to HC, patients exhibited reduced FA and increased trace and RD in the right AF, CB, and ILF. A discriminant analysis showed the possible use of FA of these tracts for better future group membership classifications. FA and RD of the right ILF and AF were associated with positive symptoms while FA and RD of the right CB were associated with memory performance and processing speed. CONCLUSION: We observed white matter alterations in the right CB, ILF, and AF, possibly caused by myelin disruptions. The structural abnormalities interact with cognitive performance, and are linked to clinical symptoms.

Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis.

BACKGROUND: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis. METHODS: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n=11). Data were analyzed using SPM8 (2-back>0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined. RESULTS: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication-naïve CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naïve CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls. CONCLUSIONS: Medication-naïve CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity.

Enlarged lateral ventricles inversely correlate with reduced corpus callosum central volume in first episode schizophrenia: association with functional measures.

The lateral and third ventricles, as well as the corpus callosum (CC), are known to be affected in schizophrenia. Here we investigate whether abnormalities in the lateral ventricles (LVs), third ventricle, and corpus callosum are related to one another in first episode schizophrenia (FESZ), and whether such abnormalities show progression over time. Nineteen FESZ and 19 age- and handedness-matched controls were included in the study. MR images were acquired on a 3-Tesla MRI at baseline and ~1.2 years later. FreeSurfer v.5.3 was employed for segmentation. Two-way or univariate ANCOVAs were used for statistical analysis, where the covariate was intracranial volume. Group and gender were included as between-subjects factors. Percent volume changes between baseline and follow-up were used to determine volume changes at follow-up. Bilateral LV and third ventricle volumes were significantly increased, while central CC volume was significantly decreased in patients compared to controls at baseline and at follow-up. In FESZ, the bilateral LV volume was also inversely correlated with volume of the central CC. This inverse correlation was not present in controls. In FESZ, an inverse correlation was found between percent volume increase from baseline to follow-up for bilateral LVs and lesser improvement in the Global Assessment of Functioning score. Significant correlations were observed for abnormalities of central CC, LVs and third ventricle volumes in FESZ, suggesting a common neurodevelopmental origin in schizophrenia. Enlargement of ventricles was associated with less improvement in global functioning over time.

Abnormal white matter connections between medial frontal regions predict symptoms in patients with first episode schizophrenia.

INTRODUCTION: The medial orbitofrontal cortex (mOFC) and rostral part of anterior cingulate cortex (rACC) have been suggested to be involved in the neural network of salience and emotional processing, and associated with specific clinical symptoms in schizophrenia. Considering the schizophrenia dysconnectivity hypothesis, the connectivity abnormalities between mOFC and rACC might be associated with clinical characteristics in first episode schizophrenia patients (FESZ). METHODS: After parcellating mOFC into the anterior and posterior part, diffusion properties of the mOFC-rACC white matter connections for 21 patients with FESZ and 21 healthy controls (HCs) were examined using stochastic tractography, one of the most effective Diffusion Tensor Imaging (DTI) methods for examining tracts between adjacent gray matter (GM) regions. RESULTS: Fractional anisotropy (FA) reductions were observed in bilateral posterior, but not anterior mOFC-rACC connections (left: p < .0001; right: p < .0001) in FESZ compared to HCs. In addition, reduced FA in the left posterior mOFC-rACC connection was associated with more severe anhedonia-asociality (rho = -.633, p = .006) and total score (rho = -.520, p = .032) in the Scale for the Assessment of Negative Symptoms (SANS); reduced FA in the right posterior mOFC-rACC connection was associated with more severe affective flattening (rho = -.644, p = .005), total score (rho = -.535, p = .027) in SANS, hallucinations (rho = -.551, p = .018), delusions (rho = -.632, p = .005) and total score (rho = -.721, p = .001) in the Scale for the Assessment of Positive Symptoms (SAPS) in FESZ. CONCLUSIONS: The observed white matter abnormalities within the connections between mOFC and rACC might be associated with the psychopathology of the early stage of schizophrenia.

Anterior commissural white matter fiber abnormalities in first-episode psychosis: a tractography study.

BACKGROUND: The Anterior Commissure (AC) is an important interhemispheric pathway that connects contralateral temporal lobes and orbitofrontal areas. The role of the AC is not yet well understood, although abnormalities in this white matter tract have been reported in patients diagnosed with chronic schizophrenia. However, it is not known whether changes in the AC are present at earlier stages of the disease. METHODS: Diffusion Magnetic Resonance Images (dMRI) were acquired from 17 First Episode Schizophrenia Patients (FESZ) and 20 healthy controls. The AC was reconstructed using a streamline tractography approach. DMRI measures, including Fractional Anisotropy (FA), Trace, Axial Diffusivity (AD) and Radial Diffusivity (RD) were computed in order to assess microstructural changes in the AC. RESULTS: FA was reduced, while trace and RD showed increases in FESZ. AD did not show differences between groups. CONCLUSION: The observed changes in these dMRI measures, namely reductions in FA and increases in trace and RD, without changes in AD, likely point to myelin abnormalities of this white matter tract, and provide evidence of white matter pathology extant in the early phases of schizophrenia.

Glucose effects on cognition in schizophrenia.

Clozapine has been shown to improve verbal declarative memory and other cognitive functions in chronic schizophrenia. This raises the possibility that additional adjunctive manipulations might improve memory further. In this study, we hypothesized that glucose, which improves memory in a variety of conditions, including schizophrenia, would improve memory more than saccharin in a group of patients stabilized on clozapine. Twelve outpatients with schizophrenia who received treatment with clozapine participated in a double-blind, counterbalanced, crossover study. Subjects received beverages containing either glucose or saccharin on one occasion, and then the other beverage about a week later. Fifteen minutes after ingesting the beverage, subjects received a brief battery of neuropsychological tests to assess verbal declarative memory, attention, and executive functions. Blood glucose levels were assessed at baseline, and at 15 and 50 min after beverage ingestion. The main findings were that retention of a list of words was improved in the glucose condition, while performance on a complex test of sustained vigilance declined after glucose ingestion. These findings provide evidence that glucose improves declarative memory in patients with schizophrenia who were treated with clozapine, and underscore the possibility of developing effective protocols to reduce cognitive dysfunctions in the disorder. They also highlight the need to explore the extent to which glucose modulates nonmemory cognitive functions such as attention, and to understand more generally how glucose availability and regulation influence cognition.

Detection and management of comorbidity in patients with schizophrenia.

Approximately half of patients with schizophrenia have at least one comorbid psychiatric or medical condition, worsening prognosis and contributing to the high rate of morbidity and mortality. Depression is associated with suicide, the leading cause of premature death in patients with schizophrenia; obsessive-compulsive symptoms may worsen prognosis; alcohol and substance use disorders are associated with a poor outcome; and comorbid medical conditions, including cardiac and pulmonary disease, infectious diseases, diabetes, hyperlipidemia, hypogonadism, and osteoporosis, are often underrecognized and undertreated. The new generation of antipsychotic medications has improved the potential outcome of patients with schizophrenia. Providing optimal treatment for patients and fully realizing the potential of these new agents require focused attention on detection, recognition, and treatment of comorbid psychiatric and medical conditions in patients with schizophrenia.

Antipsychotic medication, prolactin elevation, and ovarian function in women with schizophrenia and schizoaffective disorder.

Some, but not all, antipsychotics elevate serum prolactin. Antipsychotic-induced hyperprolactinemia is thought to account for high rates of menstrual dysfunction and diminished estrogen levels in women with schizophrenia. However, few studies have directly assessed the relationships between prolactin, menstrual function, and ovarian hormone levels in this population. Sixteen premenopausal women with schizophrenia and schizoaffective disorder, eight treated with an antipsychotic with prolactin-elevating potential (five with typical antipsychotics and three with risperidone) and eight treated with an antipsychotic with prolactin-sparing potential (seven with olanzapine and one with clozapine), were studied for eight weeks. Data were collected on menstrual functioning and on serum prolactin, estradiol, and progesterone levels, and were compared between subjects who received an antipsychotic with prolactin-elevating potential and an antipsychotic with prolactin-sparing potential, and between subjects with hyperprolactinemia (N=6) and normoprolactinemia (N=10). Additionally, peak ovarian hormone levels were compared to normal values. While mean prolactin levels of subjects who received an antipsychotic with prolactin-elevating potential were significantly greater than those of subjects who received an antipsychotic with prolactin-sparing potential, there were no differences in rates of menstrual dysfunction or in ovarian hormone values between the two groups. Additionally, similar rates of menstrual dysfunction and ovarian hormone values were observed between the hyperprolactinemic and normoprolactinemic subjects. Moreover, irrespective of medication type or prolactin status, most subjects had peak estradiol levels below normal reference values for the periovulatory phase of the menstrual cycle. While our sample size is small, warranting the need for further investigation, the findings of this preliminary study suggest that antipsychotic-induced hyperprolactinemia, alone, may not adequately explain the observed ovarian dysfunction in women with schizophrenia.