Characteristics of the child behavior checklist in adolescents with depression associated with bipolar disorder.

BACKGROUND: The child behavior checklist-Juvenile bipolar disorder phenotype (CBCL-JBD) has been proposed as a distinct profile specific to children and adolescents who have been diagnosed with bipolar disorder. The objective of this study was to examine whether bipolar disorder youth with depression exhibit the "CBCL-Juvenile bipolar disorder phenotype." METHODS: Thirty-two adolescents, ages 12-18 years, with a depressive episode associated with bipolar I disorder were recruited, and their primary caregivers completed the CBCL. RESULTS: Only the internalizing subscale (mean=70.2, SD=9.7) and total score (mean=71.5, SD=8.9) reached clinical significance (>70). Moreover, the CBCL-JBD profile scores of our subjects (204.6, SD=27.5) did not reach clinical significance (>210). LIMITATIONS: Our subjects differed demographically from those in studies that have confirmed the CBCL-Juvenile bipolar disorder phenotype with regards to sex, age and ADHD comorbidity, thus limiting the interpretability of our comparisons with other studies. Furthermore, our investigation involved a small sample size and did not include a control group, which should be addressed in future studies. CONCLUSIONS: The results of our study suggest that the CBCL-JBD profile is not characteristic of depressed youth with bipolar disorder. Better assessment tools for making an accurate and efficient diagnosis of bipolar disorder are needed so that appropriate treatment can be implemented and significant morbidity and mortality are minimized.

Functional MRI of sustained attention in bipolar mania.

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.

Differential patterns of brain activation over time in adolescents with and without attention deficit hyperactivity disorder (ADHD) during performance of a sustained attention task.

OBJECTIVE: Recent morphometric studies suggest that children with ADHD may demonstrate differential or delayed brain development compared with children without ADHD. This study examines the developmental course of brain activation patterns during the performance of an attention task. METHOD: Ten adolescents with ADHD and 14 healthy comparison adolescents performed a continuous performance task in an fMRI twice, one year apart. RESULTS: In the absence of performance differences, children with ADHD and healthy comparison subjects activated frontal-parietal regions while performing an attention task at initial testing. Children with ADHD appeared to require continued use of the right middle frontal gyrus during administration of testing one year apart while healthy comparison subjects did not activate this region at the time of the second testing. CONCLUSIONS: There appear to be developmental differences in brain activation patterns on an attentional task between ADHD and healthy controls. More research is needed for examining the longitudinal course of functional brain activation in children with ADHD.

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings.

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

Effects of acute cortisol and cocaine administration on attention, recall and recognition task performance in individuals with cocaine dependence.

This study investigated the effects of acute cocaine administration on cognition, and whether these can be modeled using exogenous hydrocortisone, because cocaine-induced cortisol elevations may influence its cognitive effects. Twelve cocaine-dependent individuals received an intravenous bolus of cortisol (0.5 or 0.2 mg/kg) and cocaine (0.2 mg/kg) in a double-blind randomized placebo-controlled and counterbalanced fashion. Cognitive testing included verbal tasks of vigilance attention, free recall and recognition memory before the boluses and at 20, 60 and 100 min thereafter. The statistical analysis investigated dose response effects while accounting for all sources of variance in the design. No effects of low dose cocaine were found on any variables. Low dose cortisol enhanced and high dose impaired vigilance attention, and a trend was found for the same dose response profile on twice-heard words. An opposite trend, inconsistent with prior research on cortisol and cognition, was observed for recognition: low dose impaired and high dose enhanced recognition of once-heard words, and a very weak trend was found for recognition of new words. These findings, though tempered by design limitations, suggest a complex non-linear cortisol attention/recognition dose-response relationship and call for further research to elucidate cortisol's effects on cognition and their role in the pathophysiology of cocaine dependence.

Age-related changes in regional activation during working memory in young adults: an fMRI study.

Several lines of evidence suggest that working memory diminishes with advancing age, with concomitant functional changes in associated neuronal activation in frontal cortical regions and hippocampi. No studies to date, however, have investigated age-related changes in neuronal activation in these regions during performance of a working memory task in younger subjects without working memory deficits. In this study, we utilized fMRI to examine changes in brain activation with increasing age in specific regions-of-interest. Eleven healthy subjects performed a "two-back" working memory task and a matched "zero-back" attention task during fMRI. There was no association between age and performance on either task. Left hippocampal activation significantly correlated with age (P = 0.01) and right hippocampal activation showed an association with age (P = 0.09). This study demonstrates that increasing age is associated with increased activation of hippocampus even in young patients without evidence of working memory deficits and suggests that functional changes may precede overt evidence of working memory deficits.

Changes in neuronal activation with increasing attention demand in healthy volunteers: an fMRI study.

Several lines of evidence suggest that structures involved in mediating attention differentially respond to increasing processing demand. Investigation of differences in neuronal activation, however, has been complicated by methodological inconsistencies and concomitant discrepancies in degree of difficulty and subject effort between disparate tasks. In this study, we utilized fMRI to compare neural activation patterns associated with two related attention tasks associated with different degrees of processing load while controlling for degree of performance difficulty. Healthy volunteers performed two continuous performance tasks, utilizing an identical pairs paradigm (CPT-IP) and a matched simple number recognition paradigm with degraded stimuli (CPT-DS) during a single fMRI scan. Degree of stimulus resolution degradation in the latter CPT was designed to equalize degree of performance difficulty between the two tasks. CPT-IP and CPT-DS were both associated with activation of frontal, limbic, subcortical, and sensory integratory structures. CPT-IP administration was associated with significantly greater activation of left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus. This study demonstrates both that differing attention tasks are associated with a high degree of functional overlap and that increasing processing demand is associated with increased activation of specific portions of attentional networks.

Comparative efficacy and tolerability of drug treatments for bipolar disorder.

Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.

Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance.

Previously, we reported progressively greater behavioral responses to repeated d-amphetamine in human subjects that represented a potential model of behavioral sensitization. To extend this work, 59 healthy volunteers were randomly assigned to one of three protocols: (1) placebo administered on days 1, 3, and 5 (PPP); (2) placebo administered on days 1 and 3, and d-amphetamine (0.25 mg/kg) on day 5 (PPA); and (3) d-amphetamine administered on days 1, 3, and 5 (AAA). Comparisons were made among the three groups to determine whether repeated d-amphetamine produced an increased behavioral response. Subjective ratings of vigor and euphoria exhibited the greatest response following the third dose of the AAA group, as hypothesized. In contrast, drug liking was greatest following a single or first d-amphetamine dose. These effects were greater in women. Progressive changes in subjective responses following repeated d-amphetamine administration may occur in healthy human subjects, although this effect may be greater for women.

Inverse relationship between plasma epinephrine and testosterone levels during acute glucoprivation in healthy men.

In healthy men, a decrease in plasma testosterone levels was observed in the context of metabolic stress. While physiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting circulating epinephrine's influence on plasma testosterone levels. The purpose of this study was to directly relate stress-induced changes in plasma testosterone and epinephrine. The stressor used was blockade of glucose metabolism with pharmacological doses (40 mg/kg) of 2 deoxyglucose (2DG). Arterial plasma samples from 10 healthy males were assayed at 20 minutes intervals for 60 minutes for the concentrations of testosterone, epinephrine and related biochemicals. Bolus administration of 2DG resulted in progressive decline in testosterone and increases in epinephrine and norepinephrine plasma levels (mean change from baseline: 29, 2530 and 186%, respectively). Inverse correlation was detected between both absolute (r(s)=-0.72; df=8; p=0.017) and baseline-corrected testosterone concentrations at the 60 minute time point and epinephrine area under the curve values. Our results suggest that adrenomedullary activation may be involved in stress-induced testosterone effects. The implications of these data for the understanding of the role of catecholamines in glucoprivic stress response are discussed.

fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder.

BACKGROUND: Previous studies suggest that a neural circuit involving over-activation of cortical, paralimbic, limbic, and striatal structures may underlie OCD symptomatology, but results may have been limited by medication use in those studies. To address this, we examined the effects of symptom induction on fMRI neural activation in medication-free patients with OCD. METHODS: Seven outpatients with OCD were exposed to individually tailored provocative and innocuous stimuli during fMRI scans. Self-ratings of OCD symptoms were performed prior to each scan and after exposure to stimuli. Images were analyzed as composite data sets and individually. RESULTS: Stimulus presentation was associated with significant increases in OCD self-ratings. Significant activation was demonstrated in several regions of the frontal cortex (orbitofrontal, superior frontal, and the dorsolateral prefrontal); the anterior, medial and lateral temporal cortex; and the right anterior cingulate. Right superior frontal activation inversely correlated with baseline compulsion symptomatology and left orbitofrontal cortical activation was inversely associated with changes in OCD self-ratings following provocative stimuli. CONCLUSIONS: These results in unmedicated patients are consistent with those from previous studies with medicated patients and suggest that OCD symptomatology is mediated by multiple brain regions including the anterior cingulate as well as frontal and temporal brain regions.

Effects of acute metabolic stress on striatal dopamine release in healthy volunteers.

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D(2)/D(3) receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p =.02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.

Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia.

OBJECTIVE: This study sought to determine whether thought disorder induced in healthy volunteers by the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine resembles the thought disorder found in patients with schizophrenia. METHOD: The Scale for the Assessment of Thought, Language, and Communication was used to assess thought disorder in healthy volunteers (N = 10) who received subanesthetic doses of ketamine and in a group of clinically stable inpatients with schizophrenia (N = 15) who did not receive ketamine. RESULTS: Mean scores on the Scale for the Assessment of Thought, Language, and Communication for patients with schizophrenia and healthy volunteers receiving ketamine did not differ significantly. Moreover, three of the four highest rated test items in both groups were the same. CONCLUSIONS: These data suggest that ketamine-induced thought disorder in healthy volunteers is not dissimilar to the thought disorder in patients with schizophrenia and provide support for the involvement of the NMDA receptor in a cardinal symptom of schizophrenia.

Effects of atypical antipsychotic drug treatment on amphetamine-induced striatal dopamine release in patients with psychotic disorders.

Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.

OBJECTIVE: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

The effects of pharmacological doses of 2-deoxyglucose on cerebral blood flow in healthy volunteers.

The effects of glucose deprivation on cerebral blood flow (CBF) have been extensively investigated during insulin-induced hypoglycemia in laboratory animals. Pharmacological doses of glucose analog, 2-deoxyglucose (2DG), is an alternative glucoprivic agent that in contrast to insulin, directly inhibits glycolysis and glucose utilization. Both glucoprivic conditions markedly increase CBF in laboratory animals. How 2DG affects CBF in humans is still undetermined. In the present study we have employed H215O positron emission tomography (PET) to examine the effects of pharmacological doses of 2DG (40 mg/kg) on regional and global cerebral blood flow in 10 brain areas in 13 healthy volunteers. 2DG administration significantly raised regional CBF (rCBF) in the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus. 2DG produced a trend towards elevated CBF in whole brain and frontal cortex, while no changes were observed in the corpus callosum and thalamus. In addition, 2DG significantly decreased body temperature and mean arterial pressure (MAP). Maximal percent changes in hypothalamic rCBF were significantly correlated with maximal changes in body temperature but not with MAP. These results indicate that cerebral glucoprivation produced by pharmacological doses of 2DG is accompanied by widespread activation of cortical and subcortical blood flow and that the blood flow changes in the hypothalamus may be related to 2DG-induced hypothermia.

Mechanism of peripheral noradrenergic stimulation by clozapine.

Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine-treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance.

Effect of acute metabolic stress on pituitary-adrenal axis activation in patients with schizophrenia.

OBJECTIVE: Although several lines of evidence suggest that stress plays a role in the course of schizophrenia, studies that have assessed stress-relevant neurobiological measures have not produced consistent results. The authors examined the effects of acute metabolic stress induced by 2-deoxy-D-glucose (2-DG) on pituitary-adrenal axis activation. METHOD: Thirteen patients with schizophrenia and 11 healthy comparison subjects were administered pharmacological doses of 2-DG (40 mg/kg). The subjects' arterial plasma was then assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. RESULTS: 2-DG induced significant increases in the measured hormones in both groups, and ACTH elevations were significantly greater in patients with schizophrenia than in comparison subjects. CONCLUSIONS: Patients with schizophrenia have an exaggerated ACTH response to acute metabolic stress exposure.

Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers.

BACKGROUND: The N-methyl-D-aspartate receptor antagonist, ketamine, produces a clinical syndrome of thought disorder, perceptual distortion, and cognitive impairment. METHODS: We have administered ketamine to healthy volunteers to characterize the formal thought disorder and specific memory dysfunction associated with ketamine. Ten healthy volunteers underwent a double-blind, placebo-controlled, ketamine infusion (0.12 mg/kg bolus and 0.65 mg/kg/hour). Thought disorder was evaluated with the Scale for the Assessment of Thought, Language and Communication. Cognitive testing involved working and semantic memory tasks. RESULTS: Ketamine produced a formal thought disorder, as well as impairments in working and semantic memory. The degree of ketamine-induced thought disorder significantly correlated with ketamine-induced decreases in working memory and did not correlate with ketamine-induced impairments in semantic memory. CONCLUSIONS: This study characterizes the formal thought disorder associated with ketamine and may suggest that ketamine-induced deficits in working memory are associated with ketamine-induced thought disorder.

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed.