Bruce K. Christensen

Depression following traumatic brain injury

OBJECTIVEnReview the existing literature on the incidence, neurobiological and psychosocial correlates, and methods of assessment and treatment of depression following traumatic brain injury (TBI).nnnDATA SOURCESnComputerized database searches of the English-language literature from Index Medicus, Psychological Abstracts, Excerpta Medica, and Cumulative Index of Nursing and Allied Health Literature.nnnSTUDY SELECTIONnGiven the relatively small number of publications specifically related to TBI and depression, all studies appearing in the peer-reviewed literature were included in the review. In addition, studies examining depression and other neurologic diseases (eg, stroke) were also reviewed as to the potential applicability of the theoretical model or methodology used.nnnCONCLUSIONSnDepression occurs with sufficient frequency to be considered a significant consequence after TBI. Depression can impede the achievement of optimal functional outcome, whether in the acute or chronic stages of recovery. It appears that a combination of neuroanatomic, neurochemical, and psychosocial factors is responsible for the onset and maintenance of depression. Its treatment is typically psychopharmacologic, with best results obtained from nontricyclic antidepressants. These results have not been confirmed in double-blind clinical trials, however. Future research should use comprehensive, integrative models of depression that include demographic, biologic, and psychosocial factors; enhanced functional neuroimaging techniques; controlled studies of psychopharmacologic and other interventions; and prospective designs with long-term follow-up.

A longitudinal study of neurocognitive function in individuals at-risk for psychosis

INTRODUCTIONnClinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established.nnnMETHODSnA comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed.nnnRESULTSnAt-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis.nnnCONCLUSIONnNeurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.

Neuropsychological status of subjects at high risk for a first episode of psychosis

Thirty-six subjects aged 16 years or older judged at risk for a first episode of psychosis within a North American multi-site study of the schizophrenia prodrome [McGlashan et al., Schizophr. Res. (2003); Miller et al., Schizophr. Res. (2003)] performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Conversely, the finding that they do not show the levels of impairment commonly observed in schizophrenia, including within the first episode, suggests that prodromal interventions might conceivably prevent, delay, or lessen the severity of declines associated with first psychotic episodes.

The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects

It has been suggested that the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are mediated through changes in cortical inhibition (CI). However, in healthy human subjects the effects of rTMS on CI have been inconsistent. Therefore, this study sought to improve on the methodological limitations of previous studies by exploring several different rTMS-stimulus conditions on inhibition in the human motor cortex. In the first experiment, 12 healthy control subjects were randomly assigned to receive regular 1, 10 or 20xa0Hz rTMS in a counterbalanced order with sessions separated by at least 1xa0week. In the second experiment, 10 of these 12 subjects received priming rTMS (600 stimuli at 6xa0Hz followed by 600 stimuli at 1xa0Hz). Cortical inhibition was indexed using short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Corticospinal excitability was indexed using motor threshold and MEP amplitude. We found no significant overall change in SICI, although there was a significant correlation between changes in SICI with baseline SICI. Subjects with greater SICI at baseline tended to have reduction in SICI post-rTMS, whereas subjects with less SICI tended to have increase in SICI post-rTMS. There was also a significant lengthening of the CSP with higher stimulation frequencies compared to lower stimulation frequencies. These findings suggest that rTMS increases CI, particularly in subjects with reduced baseline inhibition, a finding consistent with the concept of homeostatic plasticity. Baseline physiological characteristics may be further explored as a method to select patients who may benefit from rTMS treatment.

Long-Term Neurocognitive Effects of Olanzapine or Low-Dose Haloperidol in First-Episode Psychosis

BACKGROUNDnNeurocognitive deficits are severe in first-episode psychosis.nnnMETHODSnPatients (N = 263) with first-episode psychosis (schizophrenia, schizoaffective, or schizophreniform disorders) were randomly assigned to double-blind treatment with olanzapine (mean 11.30 mg/day) or haloperidol (mean 4.87 mg/day) for 104 weeks. A neurocognitive battery was administered at baseline (n = 246) and 12 (n = 167), 24 (n = 126), 52 (n = 89), and 104 (n = 46) weeks during treatment. Weighted principal component and unweighted composite scores were derived from individual tests.nnnRESULTSnBoth treatment groups demonstrated significant improvement on both composite scores. On the basis of the weighted composite score, olanzapine had greater improvement than haloperidol only at 12 (p = .014) and 24 (p = .029) weeks. For the unweighted composite, olanzapine had significantly better improvement compared with haloperidol only at week 12 (p = .044). At week 12 only, olanzapine improved performance on the Digit Symbol and Continuous Performance Test significantly more than haloperidol.nnnCONCLUSIONSnBoth antipsychotic agents appeared to improve neurocognitive functioning among first-episode psychosis patients with schizophrenia. A significantly greater benefit in terms of neurocognitive improvement was found with olanzapine than with haloperidol at weeks 12 and 24.

The use of electronic monitoring (MEMS®) to evaluate antipsychotic compliance in outpatients with schizophrenia

Compliance with antipsychotic treatment is a well-recognized concern in the ongoing management of individuals with schizophrenia. The present investigation incorporated the Medication Event Monitoring System (MEMS) to evaluate compliance in a group of outpatients (N=52) with schizophrenia or schizoaffective disorder. Evaluating compliance as a dichotomous variable and using a threshold of 80%, the rate of noncompliance as measured by MEMS was 52%, considerably higher than self-report (3%), clinician rating (24%) and pill count (25%). The ability of treating clinicians to predict compliance/noncompliance was limited: 13 of 31 (42%) subjects they rated as compliant were noncompliant while 4 of 9 (44%) rated as noncompliant were actually compliant according to MEMS. Factors most consistently associated with noncompliance were higher total symptom scores and dosing complexity i.e., greater than once daily. Based on MEMS data, the overall mean level of compliance was 66%; however, it remains unclear as to what threshold is associated with a compromise in clinical response. More sophisticated measurement tools such as MEMS may assist us in better understanding how level and pattern of antipsychotic noncompliance, factors that at present remain poorly understood, impact on symptom exacerbation.

Apathy in schizophrenia: clinical correlates and association with functional outcome

Apathy is considered one of the negative symptoms of schizophrenia, but its natural history and relationship to other clinical characteristics have not been systematically studied. The purpose of this cross-sectional study was to measure the level of apathy in schizophrenia and its relation to other symptoms and functional outcome. Twenty-eight patients with schizophrenia, and receiving antipsychotic treatment, were assessed with the Apathy Evaluation Scale (AES). The mean level of apathy of patients with schizophrenia, as rated by the AES, was significantly higher than that of matched healthy control subjects. In the patients, apathy was not significantly correlated with positive symptoms or depressive symptoms. It was significantly correlated with the item emotional withdrawal on the negative subscale of the Positive and Negative Syndrome Scale (PANSS), but was not correlated with the overall negative subscale score. Apathy was more highly associated with functional outcome than were other symptom measures, and it was independently associated with functional outcome above and beyond other negative symptoms. It was not associated with observed interest in playing a video game or performance on a simulated clerical task.

Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study

The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to [11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D(2) receptor binding potential (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.

Neuropsychological course in the prodrome and first episode of psychosis: Findings from the PRIME North America Double Blind Treatment Study

OBJECTIVEnThere is uncertainty regarding the onset timing of the cognitive deficiencies of schizophrenia. We investigated whether conversion to psychosis and/or olanzapine altered the neuropsychological course of subjects within the first-ever double blind medication study of the putative schizophrenia first episode prodrome.nnnMETHODnSixty participants in a double blind trial of olanzapine as a treatment for putative prodromal states were assessed at entry (pre-randomization), and again at 6 and 12 months (if they remained non-psychotic), or at any of these points prior to psychosis followed by post-psychosis and 6 months post-psychosis assessments.nnnRESULTSnParticipants who converted to psychosis did not differ from placebo non-converters in pre-randomization global neuropsychological status. Early converters did not differ from later converters in entry neuropsychological status. Subjects who converted after 6 months did not show neuropsychological declines during the initial, pre-psychosis, 6 months. Neuropsychological course did not differ between converters to psychosis and non-converters, or between olanzapine and placebo-assigned subjects.nnnCONCLUSIONSnNeither the onset of frank psychosis nor olanzapine treatment of the prodrome significantly alters neuropsychological course in persons considered to be at high risk at their initial (pre-psychosis) assessment. These findings suggest that the neuropsychological deficiencies associated with psychotic conditions largely pre-exist the first frank psychotic episode.

Impact of haloperidol, a dopamine D2 antagonist, on cognition and mood

Blocking dopamine (DA) D(2) receptors is the sine qua non of antipsychotic activity. However, it is this same process that accounts for their liability to produce extrapyramidal symptoms (EPS) and hyperprolactinemia. It remains unclear, though, whether there are other negative consequences that might result from DA D(2) blockade. For example, previous research has demonstrated a robust relationship between DA and both cognition and mood. The present study was designed to evaluate the impact of DA D(2) antagonism on each of these domains. Healthy participants (N = 59) were randomized to receive a single oral dose of 1, 3 or 5 mg of haloperidol or placebo. Participants were tested on cognitive and mood measures at baseline, 4 and 24 h post-administration of medication. In terms of cognition, the greatest negative impact was on sustained attention, reaction time and speed of information processing, with the effect on sustained attention reaching statistical significance. For mood, the greatest negative impact occurred on measures of contentment, anger and confusion, with the effect on contentment reaching statistical significance. Global effects for both cognition and mood domains were greatest at 4 h post-administration of haloperidol and dose-dependent. The present results suggest that DA D(2) blockade, as induced by haloperidol, produces important deficits that extend beyond motor or endocrine changes.