Debra M. Montrose

Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia

OBJECTIVE Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA(A)) receptors containing alpha(2) subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA(A) receptors containing alpha(2) subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. METHOD Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA(A) receptors containing alpha(2) or alpha(3) subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. RESULTS Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated. CONCLUSIONS These findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia : Preliminary studies

1. Studies of first-degree relatives of persons with schizophrenia provide an opportunity to characterize risk factors for the development of this illness. In this report the authors will provide preliminary data from an ongoing study of neurobiological alterations in the offspring of schizophrenia patients. 2. A series of offspring of schizophrenic patients (OS) were compared with age and sex matched healthy controls (HC) without psychiatric history in first degree relatives on psychiatric, volumetric Magnetic Resonance Imaging (MRI) of whole brain and proton Magnetic Resonance Spectroscopy (1H MRS) evaluations of the ventral prefrontal cortex. 3. Compared with HC group, high risk subjects had reduced left amygdala volume, enlarged third ventricular volume, and smaller overall brain volume. 4. 1H MRS studies showed a trend for decreased NAA/choline ratios in the anterior cingulate region in the OS group as compared to HC subjects. 5. Follow-up studies of these subjects are needed to confirm the predictive value of these measures for future emergence of schizophrenia in subjects at risk for this illness.

Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia

Abnormalities in the structural integrity and connectivity of the medial temporal and the prefrontal cortex are well documented in schizophrenia, but it is unclear if they represent premorbid indicators of neuropathology. Studies of young relatives at high-risk for schizophrenia (HR) provide an opportunity to clarify this question. We herein provide data from a magnetic resonance imaging (MRI) study of these structures in young offspring of schizophrenia patients. A series of 17 young HR offspring of schizophrenic patients were compared with 22 healthy comparison subjects (HC). Morphometric comparisons of the right and left dorsolateral prefrontal cortex (DLPFC), and the anterior and posterior amygdala-hippocampal (A-H) complex were conducted using high-resolution whole brain T(1) weighted brain images. Compared with the HC group, HR subjects had significant decreases in intracranial volume. The volumes of the left anterior and posterior A-H complex were reduced in the HR subjects after adjusting for intracranial volume. HR subjects also showed a significant leftward (Right>Left) asymmetry of the anterior A-H complex compared to the HC subjects. No significant changes were seen in the DLPFC. Thus, lateralized alterations in the volume of the left A-H complex are evident in unaffected young offspring of schizophrenia patients and may be of neurodevelopmental origin. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

Social Cognition Deficits Among Individuals at Familial High Risk for Schizophrenia

Social cognition in young relatives of schizophrenia probands (N=70) and healthy controls (N=63) was assessed using the Penn Emotion Recognition Test-40 to examine the presence of social cognitive deficits in individuals at risk for the disorder. Measures of neurocognitive function and prodromal psychopathology were collected to assess the cognitive and clinical correlates of social cognitive impairments in at-risk relatives. Results indicated that when compared with healthy controls, individuals at familial high risk for schizophrenia were significantly more likely to overattribute emotions to neutral faces, with such individuals frequently misinterpreting neutral faces as negative. In addition, at-risk individuals had significantly greater reaction times when completing emotion recognition tasks, regardless of valence. Impairments in neurocognition were largely independent of social cognitive performance, and emotion recognition impairments persisted after adjusting for deficits in neurocognitive function. Further, social cognitive impairments in the interpretation of neutral faces were significantly associated with greater positive and general prodromal psychopathology, whereas neurocognitive impairments were only associated with disorganization. These results suggest that impairments in social cognition may be unique endophenotypes for schizophrenia.

Cannabis use and brain structural alterations in first episode schizophrenia — A region of interest, voxel based morphometric study

Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors. Among the environmental factors, cannabis use has been associated with increased risk for patients with schizophrenia, but the effect of cannabis on their brain structure is unclear. We examined gray matter alterations in first episode schizophrenia patients (FES) with cannabis use (FES+C; n=15) compared to FES without cannabis use (FES-C; n=24) and 42 healthy controls who did not use cannabis. We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions. We observed a decrease in gray matter density in the right posterior cingulate cortex (PCC) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure, in particular regions rich in CB1 receptors. These findings need to be confirmed by larger, prospective studies.

Decreased BDNF in Patients with Antipsychotic Naïve First Episode Schizophrenia

OBJECTIVE Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls. METHOD Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls. RESULTS A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning. CONCLUSIONS Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis.

Psychopathology among offspring of parents with schizophrenia: Relationship to premorbid impairments

INTRODUCTION A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia. METHODS Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information. RESULTS Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy. DISCUSSION A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.

Genetically predisposed offspring with schizotypal features: An ultra high-risk group for schizophrenia?

Biomarkers proposed in the schizophrenia diathesis have included neurocognitive deficits in domains such as working memory that implicate prefrontal systems. However, the relationship between these biomarkers and psychopathological markers such as schizotypy has not been systematically assessed, particularly in adolescent offspring of schizophrenia patients. Convergence between these markers may identify individuals at especially high risk for schizophrenia. In the current study the authors assessed whether functional deficits in working memory assessed using the oculomotor delayed response task (ODR) and executive function assessed using the Wisconsin Card Sort task (WCST), and structural deficits in prefrontal cortex, in the adolescent offspring of patients were predictive of schizotypy. Schizotypal offspring made more perseverative errors on the WCST (p<.002) and showed age-related deficits on the ODR task (p<.02) compared to their non-schizotypal counterparts or healthy controls. Reduced gray matter concentration in prefrontal cortex (p<.001) was also associated with schizotypy. Schizotypy in offspring of schizophrenia patients appears to be highly associated with known biomarkers of the illness such as executive function impairment and reductions in cortical gray matter. Furthermore, schizotypy appears to interact with development leading to greater impairment in working memory in schizotypal offspring closer to the typical age of onset of schizophrenia than non-schizotypal offspring. Thus, clinical and neurocognitive biomarkers of the illness appear to be highly interrelated in this sample of at-risk offspring. We propose that schizotypy may define a hyper vulnerable sub-sample among individuals genetically predisposed to schizophrenia and that future studies that attempt to assess risk may benefit from such a convergent approach.

Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n=25) and healthy controls (HC, n=30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P=0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values<0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp–5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp–5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.