James S. Olver

A manual and automated MRI study of anterior cingulate and orbito-frontal cortices, and caudate nucleus in obsessive-compulsive disorder: Comparison with healthy controls and patients with schizophrenia

Functional imaging and neuropsychological data suggest that interconnected brain structures including the orbito-frontal cortex (OFC), anterior cingulate cortex (ACC) and caudate nucleus (CN) are involved in the pathophysiology of obsessive-compulsive disorder (OCD), but structural imaging studies investigating these regions have yielded inconclusive results. This may be due to inconsistencies in the identification of anatomical boundaries and methodologies utilised (i.e. automated vs. manual tracing). This magnetic resonance imaging study used manual tracing to measure volumes of selected brain regions (OFC, ACC and CN) in OCD patients and compared them with samples of healthy (HC) and psychiatric (schizophrenia; SCZ) controls (n=18 in each group). Concurrently, automated voxel-based analysis was also used to detect subtle differences in cerebral grey and white matter. For the OCD vs. HC comparison, there were no significant volumetric differences detected using the manual or the automated method (although the latter revealed a deficit in the subcortical white matter of the right temporal region). A direct comparison of the two patient groups showed no significant differences using the manual method. However, a moderate effect size was detected for OFC grey matter (reduced in SCZ), which was supported by findings of reduced OFC volume in the automated analysis. Automated analyses also showed reduced volumes in the dorsal (white matter) and ventral ACC (grey and white matter), as well as the left posterior cingulate (grey and white matter) in SCZ. The findings suggest that in contrast to findings in SCZ, there are very few (if any) gross structural anomalies in OCD.

A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia

This study examined the criterion and construct validity of a brief computerized cognitive test battery (CogState Schizophrenia Battery) compared to a conventional cognitive test battery recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus. The CogState and MATRICS batteries yielded comparable effect sizes in comparing patients with schizophrenia to healthy controls (Cohens ds = −1.50 for both batteries). Moderate to large correlations were observed between CogState and MATRICS measures of processing speed, attention/vigilance, working memory, verbal and visual learning, reasoning/problem solving, and social cognition (rs = .56–.79). CogState and MATRICS composite scores also correlated strongly with scores on the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA; rs = .76 and .79, respectively) in patients with schizophrenia. Results of this study suggest that the CogState Schizophrenia Battery provides valid measurement of the cognitive domains nominated by the MATRICS consensus group as being important to consider in the context of pharmacological treatments for cognitive impairment in schizophrenia.

Selective effects of acute serotonin and catecholamine depletion on memory in healthy women.

There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.

Behavioural studies of spatial working memory dysfunction in schizophrenia: a quantitative literature review.

Cognitive impairments in schizophrenia have been recognized as a prominent feature of the illness. Research is now focusing on determining a relationship between neurocognitive impairments, and social and functional outcome. Despite a number of comprehensive reviews on neurocognitive measures and reports on spatial working memory abnormalities in patients with schizophrenia when compared to healthy volunteers, there have been no meta-analyses of the extent of the abnormality in this group of patients. We reviewed 33 studies (from 1992 to 2005) on spatial working memory impairment in schizophrenia with the aim of providing a quantitative assessment of the consistency and the magnitude of the deficit. From the quantitative data analysis, it is evident that patients with schizophrenia are consistently more impaired on the spatial working memory measures than healthy controls. These impairments may be related to social disability and explain some cognitive deficits that characterize the clinical presentation of schizophrenia.

Depression and physical illness.

Depressive symptoms frequently accompany physical illness, but the association between the two is complex. The combination has detrimental implications for the patients health outcome, quality of life, medical treatment and health care use. The presence of physical symptoms of the medical illness can lead to challenges in recognising and diagnosing depression. This is best dealt with by placing greater emphasis on the psychological symptoms of depression. Recognition may be improved through use of appropriate screening tools for depression in medically ill patients. The management of depression in the setting of medical illness involves both general and specific approaches. General approaches include optimal treatment of the medical illness, exclusion of treatments that are associated with depressive symptoms, and simple general health strategies aimed at improving sleep and exercise. Good evidence exists for selective psychotherapeutic approaches and antidepressant treatments, but care is required to avoid drug-drug and illness-drug interactions with the latter.

Dopamine D1 receptor binding in the striatum of patients with obsessive–compulsive disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder of unknown aetiology. Psychopharmacological studies have suggested a role for the neurotransmitter serotonin however further evidence for serotonin in the aetiology of OCD is conflicted. The authors used positron emission tomography (PET) to examine the binding of the dopamine D(1) receptor antagonist [(11)C]-SCH23390 to D(1) receptors in the striatum of drug-free OCD patients compared with healthy controls. METHODS Seven drug-free patients (two drug naïve) with OCD and seven age, gender and education matched healthy controls underwent positron emission tomography with [(11)C]-SCH23390. Binding Potentials (BP) at D(1) receptors were calculated for the caudate nucleus and putamen. Correlations between BP values for basal ganglia regions and clinical measures were performed in OCD patients. RESULTS The BP for [(11)C]-SCH23390 at D(1) receptors in OCD patients was significantly reduced in both caudate nucleus (0.59+/-0.06 vs 0.88+/-0.06, p<0.05) and putamen (0.89+/-0.06 vs 1.14+/-0.06, p<0.05) compared with healthy controls. No correlations were found between D(1) BP and symptom measures. LIMITATIONS The main limitations of this study are the small sample size and the PET methodology which does not allow for disaggregation of Bmax and Kd values for D(1) receptor binding of [(11)C]-SCH23390. CONCLUSIONS The finding of downregulation of D(1) receptors in the striatum of OCD patients suggests increased nigrostriatal dopaminergic drive in OCD. If confirmed, this finding provides support for trials of novel treatments in OCD based on dopaminergic system blockade.

Effect of Sodium Valproate on Nocturnal Melatonin Sensitivity to Light in Healthy Volunteers

Sensitivity of the pineal hormone melatonin to bright light at night has been proposed as a putative marker of bipolar affective disorder. Patients with bipolar disorder have a super-sensitive melatonin response to light. No studies have investigated whether super-sensitivity is due to agents used to treat the illness or is associated with the disorder per se. We investigated the effect of valproate on this phenomenon. Melatonin sensitivity to light was determined on two nights in 12 healthy volunteers (5M, 7F). Between testing nights participants received 200 mg of valproate b.d. for 5 days. Valproate significantly decreased the sensitivity of melatonin to light. On the other hand, valproate had no effect on overall melatonin secretion or dim light melatonin onset. The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder—an ability to lengthen circadian period similar to that of lithium.

Third-generation antidepressants Do they offer advantages over the SSRIs?

Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements.Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been posited as a putative marker of affective disorders. Research demonstrates melatonin supersensitivity to light in bipolar disorder, however the role that lithium carbonate plays in this response is unclear. This study assessed the effect of lithium on nocturnal melatonin secretion and sensitivity to light in healthy adults. Ten participants, tested on two nights, had blood samples drawn between 20:00 and 02:30 hours. On testing nights participants were exposed to 200 lux of light between 24:00 and 01:00 hours. Participants took 250 mg of lithium daily for 5 d between testing nights. The results indicated that lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis. This finding has implications on the true magnitude of the melatonin light response in people with bipolar disorder and may elucidate possible mechanisms of action of lithium.