Deborah Medoff

Increased cortical kynurenate content in schizophrenia.

BACKGROUND Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3-hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function.

Ketamine activates psychosis and alters limbic blood flow in schizophrenia

The non-competitive NMDA antagonist ketamine, given to schizophrenic individuals in subanesthetic doses, produced a short-lived, discrete activation of their psychotic symptoms, which had striking similarities to symptoms of their usual psychotic episodes. To further study this psychotomimetic property of ketamine, we administered 0.3 mg kg−1 of the drug to schizophrenic individuals during a [15O] water cerebral blood flow study. Regional cerebral blood flow (rCBF) was measured using H215O and positron emission tomography (PET) before and after ketamine administration to identify regions of flow change. rCBF was increased in anterior cingulate cortex and was reduced in the hippocampus and primary visual cortex (lingual and fusiform gyri). These data encourage further consideration of altered glutamatergic transmission in schizophrenic and PCP-induced psychoses.

Functional effects of antipsychotic drugs: Comparing clozapine with haloperidol

BACKGROUND Using positron emission tomography (PET) with (15)O water, we compared regional cerebral blood flow (rCBF) patterns induced by clozapine or haloperidol in individuals with schizophrenia. Based on the known clinical characteristics of each drug, we hypothesized that brain regions where the drugs show similar rCBF patterns are among those mediating their antipsychotic actions; whereas, regions where the drugs produce different rCBF patterns are among those mediating their different drug actions, namely, haloperidols motor side effects or clozapines unique therapeutic action. METHODS Persons with schizophrenia were scanned using PET with (15)O water, first after withdrawal of all psychotropic medication (n = 6), then again after treatment with therapeutic doses of haloperidol (n = 5) or clozapine (n = 5). RESULTS Both drugs increased rCBF in the ventral striatum and decreased rCBF in hippocampus and ventrolateral frontal cortex. The rCBF increase associated with haloperidol was greater than that with clozapine in the dorsal and ventral striatum; the rCBF increase with clozapine was greater than that with haloperidol in cortical regions, including anterior cingulate and dorsolateral frontal cortex. CONCLUSIONS These data suggest that the rCBF increase in ventral striatum and/or the decrease in hippocampus and/or ventrolateral frontal cortex mediate a common component of antipsychotic action of these drugs. The increased rCBF in dorsal striatum by haloperidol could well be associated with its prominent motor side effects, whereas the increased rCBF in the anterior cingulate or dorsolateral frontal cortex may mediate the superior antipsychotic action of clozapine. The proposals based on these preliminary observations require further study.

Sequential Regional Cerebral Blood Flow Brain Scans Using PET with H215O Demonstrate Ketamine Actions in CNS Dynamically

The aim of this study was to examine the potential of serial rCBF studies to directly characterize the regional effects and dynamic time course of the centrally active drug ketamine. The value of a broader application of this technique to other neurally active drugs to characterize the pharmacodynamics of CNS compounds is suggested by these data. Thirteen normal subjects received a 0.3 mg/kg intravenous dose of ketamine over 60 seconds; ten other individuals received placebo in the same manner. For each subject, three baseline PET rCBF scans and seven sequential post-ketamine scans at 10-minute intervals were obtained using H215O water. SPM techniques were employed to identify the maxima of any cluster significant by spatial extent analysis at any post-ketamine time point between 0 and 36 min. These extremes from the ketamine group, were identified in placebo scans similarly and grown to a 6x6x12 mm voxel set. The average rCBF values of the ketamine-defined clusters were determined in the drug and placebo conditions at all time points. rCBF across time was plotted for each cluster and compared between drug and placebo. Area under the curve (AUC) was calculated between baseline and 36 minutes. The kinetic characteristics of the ketamine-induced rCBF curves were compared to induced behaviors in each maxima. Ketamine produced distinct patterns of rCBF change over time in different brain regions; maxima within an anatomically defined region responded similarly. Ketamine induced rCBF activations in anterior cingulate, medial frontal and inferior frontal cortices. All maxima with a relative flow reduction with ketamine were in the cerebellum. The pattern of all activations and suppressions was monophasic with the peak changes at 6–16 minutes. In preliminary analysis, individual Cmax and AUC of maxima in the anterior cingulate/medial frontal region tended to correlate with the mild psychotomimetic action of ketamine; whereas, there was no tendency toward correlation with this psychological change in cerebellar maxima. The direct action of a centrally active drug can be assessed regionally and dynamically in brain using rCBF and a scan sequence optimally timed to complement the drugs time course. Ketamine pharmacodynamic response can be related to concurrent behavioral changes, tending to link the behavior with a brain region. This experimental design provides direct characterization of drug action in the CNS in ways heretofore unavailable.

Outcomes of a Randomized Study of a Peer-Taught Family-to-Family Education Program for Mental Illness

OBJECTIVE The Family-to-Family Education Program (FTF) is a 12-week course offered by the National Alliance on Mental Illness (NAMI) for family members of adults with mental illness. This study evaluated the courses effectiveness. METHODS A total of 318 consenting participants in five Maryland counties were randomly assigned to take FTF immediately or to wait at least three months for the next available class with free use of any other NAMI supports or community or professional supports. Participants were interviewed at study enrollment and three months later (at course termination) regarding problem- and emotion-focused coping, subjective illness burden, and distress. A linear mixed-effects multilevel regression model tested for significant changes over time between intervention conditions. RESULTS FTF participants had significantly greater improvements in problem-focused coping as measured by empowerment and illness knowledge. Exploratory analyses revealed that FTF participants had significantly enhanced emotion-focused coping as measured by increased acceptance of their family members illness, as well as reduced distress and improved problem solving. Subjective illness burden did not differ between groups. CONCLUSIONS This study provides evidence that FTF is effective for enhancing coping and empowerment of families of persons with mental illness, although not for reducing subjective burden. Other benefits for problem solving and reducing distress are suggested but require replication.

Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia

Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n=13) and medicated volunteers with schizophrenia (n=10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with 15O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70–80% accuracy. They were then scanned during three task conditions: (1) Rest, (2) sensory motor control (SMC) task, and (3) decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

Intra-Individual Variability Among Children with ADHD on a Working Memory Task: An Ex-Gaussian Approach

Intra-individual variability on a computer-based working memory task was examined among 25 children/adolescents with ADHD and 24 typically developing peers. Participants completed the Visual Serial Addition Task (VSAT) and reaction time data were fit to an ex-Gaussian distribution. ADHD participants demonstrated significantly more variable performance than controls, and effects of working memory load were observed. Event rate, however, had no influence on group differences in performance. Follow-up correlations revealed associations between VSAT performance and ADHD symptomatology. This study supports intra-individual variability as a hallmark feature of ADHD beyond the domain of response inhibition and reinforces the need to consider variability in ADHD more broadly.

Use of the internet and other media for health information among clinic outpatients with serious mental illness

OBJECTIVE This study examined how people with serious mental illness access and use media to receive health information. METHODS One hundred people with serious mental illness were interviewed regarding their media use, with a focus on how they get their health information. RESULTS Among these participants, 91% had a television (M+/-SD=5.7+/-4.6 hours per day), and 74% indicated it was a primary health information source. One third of the sample had used the Internet. Of these participants, about half (53%) had gone online for health information. Younger participants and those with more education were significantly more likely to use the Internet. Among Internet nonusers, there was still interest in finding health information online; however, expense, lack of computer skills or knowledge, and difficulties with typing and reading prevented doing so. CONCLUSIONS Although this sample used television more often than the Internet as a resource, there appears to be interest among persons with serious mental illness in using the Internet as a source of health information and support.

Smooth pursuit eye movements to extra-retinal motion signals: deficits in patients with schizophrenia

In order to understand mechanisms underlying the smooth pursuit abnormality(ies) in schizophrenia, new methods, which independently evaluated predictive smooth pursuit responses to extra-retinal motion signals, were developed and tested. The study compared responses to only extra-retinal motion signals in normal volunteers (n = 25), and individuals with a chronic (n = 21) and a recent onset (n = 18) schizophrenia. Subject groups with chronic schizophrenia and recent onset schizophrenia had significantly poorer predictive pursuit than normal subjects in response to only extra-retinal motion signals. The poor predictive pursuit was evident even at low target velocity when the closed-loop pursuit gain was normal in patients with schizophrenia. Ten of the 18 recent onset patients were drug-free at the time of testing and had no or minimum previous exposure to anti-psychotic medications. Re-analyses of the data showed that on most measures of predictive pursuit, drug-free patients were not significantly different from patients who received anti-psychotic drug treatment. Both patient groups had significantly poorer predictive pursuit than normal subjects. These results suggest that a deficit in processing extra-retinal motion may underlie the abnormal smooth pursuit response in schizophrenia. At low target velocities, patients with schizophrenia were able to compensate for the low extra-retinal gain by increasing the gain of response to the retinal slip velocity. This indicates that patients were able to process retinal slip velocity and generate smooth pursuit eye movements, but experienced a specific deficit in processing and/or integrating extra-retinal motion information for the smooth pursuit response.