The effects of benzodiazepines on cognition

Initially thought to be virtually free of negative effects, benzodiazepines are now known to carry risks of dependence, withdrawal, and negative side effects. Among the most controversial of these side effects are cognitive effects. Long-term treatment with benzodiazepines has been described as causing impairment in several cognitive domains, such as visuospatial ability, speed of processing, and verbal learning. Conversely, long-term benzodiazepine use has also been described as causing no chronic cognitive impairment, with any cognitive dysfunction in patients ascribed to sedation or inattention or considered temporary and associated with peak plasma levels. Complicating the issue are whether anxiety disorders themselves are associated with cognitive deficits and the extent to which patients are aware of their own cognitive problems. In an attempt to settle this debate, meta-analyses of peer-reviewed studies were conducted and found that cognitive dysfunction did in fact occur in patients treated long term with benzodiazepines, and although cognitive dysfunction improved after benzodiazepines were withdrawn, patients did not return to levels of functioning that matched benzodiazepine-free controls. Neuroimaging studies have found transient changes in the brain after benzodiazepine administration but no brain abnormalities in patients treated long term with benzodiazepines. Such findings suggest that patients should be advised of potential cognitive effects when treated long term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients.     

Meeting report: transcranial magnetic stimulation and studies of human cognition

A James S. McDonnell Foundation workshop examined the role of TMS in studies of human cognition. A summary of the workshop presentations, discussion, and the recommendations appear below. A selected reference list is provided at the end of the summary.     

Muscarinic M1 receptor sequence: preliminary studies on its effects on cognition and expression

It has been reported that people with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism of the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test than those who are heterozygous. We investigated whether CHRM1 sequence is associated with impaired executive function, a common problem in schizophrenia. We sequenced the CHRM1 using peripheral DNA from 97 people with schizophrenia who completed the Wisconsin Card Sorting Test, a verbal fluency test and the National Adult Reading Test. Clinical severity was assessed using the Positive and Negative Syndrome Scale. To determine whether CHRM1 sequence affected receptor expression, we used post-mortem data, from another cohort, to investigate associations between CHRM1 sequence and mRNA levels. On the Wisconsin Card Sorting Test, 267C/C participants with schizophrenia made more perseverative errors (p<0.05) and perseverative responses (p<0.05) than 267C/A participants. Genotype had no effect on verbal fluency (p=0.8) or National Adult Reading test (p=0.62). Cortical CHRM1 mRNA levels did not vary with gene sequence (p=0.409). The clinical study supports the proposal that CHRM1 sequence is associated with alterations in some aspects of executive function. However, the post-mortem study indicates this is not simply due to altered expression at the level of mRNA, suggesting this sequence alteration may affect the functionality of the CHRM1.     

Dynamically changing effects of corticosteroids on human hippocampal and prefrontal processing

Stress has a powerful impact on memory. Corticosteroids, released in response to stress, are thought to mediate, at least in part, these effects by affecting neuronal plasticity in brain regions involved in memory formation, including the hippocampus and prefrontal cortex. Animal studies have delineated aspects of the underlying physiological mechanisms, revealing rapid, nongenomic effects facilitating synaptic plasticity, followed several hours later by a gene‐mediated suppression of this plasticity. Here, we tested the hypothesis that corticosteroids would also rapidly upregulate and slowly downregulate brain regions critical for episodic memory formation in humans. To target rapid and slow effects of corticosteroids on neural processing associated with memory formation, we investigated 18 young, healthy men who received 20 mg hydrocortisone either 30 or 180 min before a memory encoding task in a double‐blind, placebo‐controlled, counter‐balanced, crossover design. We used functional MRI to measure neural responses during these memory encoding sessions, which were separated by a month. Results revealed that corticosteroids' slow effects reduced both prefrontal and hippocampal responses, while no significant rapid actions of corticosteroids were observed. Thereby, this study provides initial evidence for dynamically changing corticosteroid effects on brain regions involved in memory formation in humans. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

No evidence for direct modulatory effects of delta 9-tetrahydrocannabinol on human polymorphonuclear leukocytes

The effects of cannabinoids (CB) that have been reported in various leukocyte populations were mainly immunosuppressive or immunomodulatory. Almost nothing is known, however, about direct interactions of cannabinoids with human polymorphonuclear cells (PMN), although m-RNA for the cannabinoid receptor-2 (CB(2)) was found in human PMN. In order to investigate a potential influence of cannabinoids on human PMN, the migration and phagocytosis of PMN were studied in the presence of Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) at final concentrations between 10(-10) and 10(-5) M. No effect was detectable on these essential PMN functions; and besides, no CB(2)-receptor expression could be detected using the Western blotting technique. Thus, circulating human PMN from healthy individuals remain unaffected by Delta(9)-THC due to the absence of functional CB(2)-receptor expression.     

The effects of levetiracetam on cognition: A non-interventional surveillance study

Objective and subjective cognitive measures were evaluated in 401 patients before and 3 and 6 months after introducing levetiracetam (LEV). Initially, cognitive impairment was indicated in 37–44% of the patients, and subjective impairments in 32–67%. With LEV, 87% of untreated patients changed to monotherapy, and 94% changed from mono- to polytherapy. The rate of retention of LEV was 97%; adverse events were reported by 7%. Under LEV, 36% achieved early seizure control, 25% achieved late seizure control, 33% continued to have seizures, and 7% had a relapse. Very good tolerance was reported by 68%, and cognitive improvement by 58%. Objective improvement was significant in 23–29% of the patients; 5–6% deteriorated. Better baseline scores, later-onset epilepsies, fewer initial antiepileptic drugs, and seizure control were predictive of a better cognitive outcome. Considering the uncontrolled study design and the increase in total drug load, LEV appeared safe and efficacious, and a general subjective and objective cognitive improvement could be noted. However, a controlled study design would be required to attribute these improvements to a specific drug action.     

The effects of levetiracetam on cognition: a non-interventional surveillance study

Objective and subjective cognitive measures were evaluated in 401 patients before and 3 and 6 months after introducing levetiracetam (LEV). Initially, cognitive impairment was indicated in 37–44% of the patients, and subjective impairments in 32–67%. With LEV, 87% of untreated patients changed to monotherapy, and 94% changed from mono- to polytherapy. The rate of retention of LEV was 97%; adverse events were reported by 7%. Under LEV, 36% achieved early seizure control, 25% achieved late seizure control, 33% continued to have seizures, and 7% had a relapse. Very good tolerance was reported by 68%, and cognitive improvement by 58%. Objective improvement was significant in 23–29% of the patients; 5–6% deteriorated. Better baseline scores, later-onset epilepsies, fewer initial antiepileptic drugs, and seizure control were predictive of a better cognitive outcome. Considering the uncontrolled study design and the increase in total drug load, LEV appeared safe and efficacious, and a general subjective and objective cognitive improvement could be noted. However, a controlled study design would be required to attribute these improvements to a specific drug action.     

WHI and WHIMS follow-up and human studies of soy isoflavones on cognition

Recent follow-up analyses of the previous findings from the Women's Health Initiative and the Women's Health Initiative Memory Study confirmed some health benefits of estrogen-containing hormone therapy (HT) in women within 10 years from the onset of menopause. However, the potential risks associated with long-term administration of HT, such as breast cancer and stroke, remain a concern for therapy recipients, underlying the need for an alternative treatment that is functionally equivalent but with a greater safety profile. Owing to their structural and functional resemblance to mammalian estrogens and lack of evident adverse effects, research interest in plant-derived phytoestrogens has increased in the past decade. While multiple health-promoting benefits of phytoestrogens have been proposed from basic science, the clinical data remain inconclusive. This review provides a comparative analysis of human studies on the effects of soy-based isoflavones on cognition. Of the eight studies published in 2000-2007, seven were conducted in postmenopausal women, four of which revealed a positive impact of isoflavones on cognitive function. Multiple factors could have contributed to the discrepant outcomes across studies, such as variation in the composition of phytoestrogen interventions and the heterogeneous characteristics of the study population. Thus, a well-designed clinical study based on a standardized stable formulation in a well-characterized study population is required in order to reach a clinical consensus. A formulation composed of select estrogen receptor beta-selective phytoestrogens with a rationally designed composition would avoid the potential antagonism present in a mixture and thus enhance therapeutic efficacy. In addition, inclusion of equol in a study formulation offers a potential synergistic effect from equol in both equol-producing and nonproducing individuals, as well as added benefits for men. With respect to the design of study population, a clinically consistent effect could potentially be achieved by stratifying populations based on genotype, age, hormonal history and even diets. Development of an effective phytoestrogen formulation would benefit both women and men to prevent or treat hormone-dependent conditions and, most of all, to improve neurological health and reduce the risk of Alzheimer's disease.     

Genetic effects on human cognition: lessons from the study of mental retardation syndromes

The molecular basis of human cognition is still poorly understood, but recent advances in finding genetic mutations that result in cognitive impairment may provide insights into the neurobiology of cognitive function. Here we review the progress that has been made so far and assess what has been learnt from this work on the relation between genes and cognitive processes. We review evidence that the pathway from genetic lesion to cognitive impairment can be dissected, that some genetic effects on cognition are relatively direct and we argue that the study of mental retardation syndromes is giving us new clues about the biological bases of cognition.     

Longitudinal studies of cognition in schizophrenia: meta-analysis

BACKGROUND: A wide range of cognitive deficits have been demonstrated in schizophrenia, but their longitudinal course remains unclear. AIMS: To bring together all the available information from longitudinal studies of cognitive performance in people with schizophrenia. METHOD: We carried out a meta-analysis of 53 studies. Unlike previous reviewers, we included all studies (regardless of the type of medication), analysed each variable separately and compared results with data from controls. RESULTS: Participants with schizophrenia showed a significant improvement in most cognitive tasks. The available data for controls showed, with one exception (the Stroop test), a similar or greater improvement. Performance in semantic verbal fluency remained stable in both individuals with schizophrenia and controls. CONCLUSIONS: Participants with schizophrenia displayed improvement in most cognitive tasks, but practice was more likely than cognitive remediation to account for most of the improvements observed. Semantic verbal fluency may be the best candidate cognitive endophenotype.     

The effects of antiepileptic drugs on cognition in normal volunteers

Abstract The effects of antiepileptic drugs on cognitive function in 48 healthy volunteers were assessed using event-related potentials (ERP) and the Attention Index included in the Wechsler Memory Scale, revised edition (WMS-R). The study was conducted over 1 week, using a double-blind design. Four drugs, carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and zonisamide (ZNS) were tested. Using an auditory oddball task, ERP measurements were made under two conditions with different tone intensities: Condition 1 used 70 db SPL; and Condition 2 used 30 db SPL. Results showed that CBZ prolonged target N1 and P3 latencies in Condition 1, and reduced frequent N1 amplitude in Condition 2, which suggests that CBZ may cause a change in sensory memory and prolong stimulus evaluation time. It is suggested that under a low stimulus intensity level, the sensory function itself was affected. Phenytoin was found to prolong target N1 latency in Condition 2, which also indicates a change in the sensory memory function. However, VPA did not significantly affect ERP components, except for the shortened frequent N1 latency, which could not be explained due to the limited information. It was found that ZNS augmented P3 amplitude in Condition 2, and reduced scores on the Attention Index. It is suggested that the augmentation of P3 amplitude was caused by the reduction of processing negativity as a result of the detrimental effect of ZNS on subjects' attention. However, the apparent difference between the ERP and behavioral indices suggests that caution should be exercised in assessing the results obtained only from ERP measurements.     

The role of dopamine in cognition: evidence from functional imaging studies

Functional imaging provides a sensitive means of studying the dopaminergic system in the brain. Both pre-synaptic and post-synaptic aspects of this system can be explored, and recent technical advances even allow the estimation of the synaptic level of dopamine in the striatum. However, only a few studies have used functional imaging to identify the role of dopamine in cognition. This paper reviews recent evidence provided by studies in healthy individuals and patients with Parkinson's disease or schizophrenia supporting the role of dopamine in normal and pathological cognitive processes.     

Glucose effects on cognition in schizophrenia

Clozapine has been shown to improve verbal declarative memory and other cognitive functions in chronic schizophrenia. This raises the possibility that additional adjunctive manipulations might improve memory further. In this study, we hypothesized that glucose, which improves memory in a variety of conditions, including schizophrenia, would improve memory more than saccharin in a group of patients stabilized on clozapine. Twelve outpatients with schizophrenia who received treatment with clozapine participated in a double-blind, counterbalanced, crossover study. Subjects received beverages containing either glucose or saccharin on one occasion, and then the other beverage about a week later. Fifteen minutes after ingesting the beverage, subjects received a brief battery of neuropsychological tests to assess verbal declarative memory, attention, and executive functions. Blood glucose levels were assessed at baseline, and at 15 and 50 min after beverage ingestion. The main findings were that retention of a list of words was improved in the glucose condition, while performance on a complex test of sustained vigilance declined after glucose ingestion. These findings provide evidence that glucose improves declarative memory in patients with schizophrenia who were treated with clozapine, and underscore the possibility of developing effective protocols to reduce cognitive dysfunctions in the disorder. They also highlight the need to explore the extent to which glucose modulates nonmemory cognitive functions such as attention, and to understand more generally how glucose availability and regulation influence cognition.     

The effects of unilateral forced nostril breathing on cognition

Ultradian rhythms of alternating cerebral dominance have been demonstrated in humans and other mammals during waking and sleep. Human studies have used the methods of psychological testing and electroencephalography (EEG) as measurements to identify the phase of this natural endogenous rhythm. The periodicity of this rhythm approximates 1.5-3 hours in awake humans. This cerebral rhythm is tightly coupled to another ultradian rhythm known as the nasal cycle, which is regulated by the autonomic nervous system, and is exhibited by greater airflow in one nostril, later switching to the other side. This paper correlates uninostril airflow with varying ratios of verbal/spatial performance in 23 right-handed males. Relatively greater cognitive ability in one hemisphere corresponds to unilateral forced nostril breathing in the contralateral nostril. Cognitive performance ratios can be influenced by forcibly altering the breathing pattern.     

The effects of alcohol on cognition in the elderly: from protection to neurodegeneration

The effects of chronic alcohol abuse on cognition are well known. Memory and executive functions appear to be the cognitive domains primarily impaired, and prefrontal and frontal damage is reported on neuroimaging studies both at micro- and macrostructural levels. Abstinence can partially reverse these alterations through mechanisms of neuroplasticity. Alcohol acts in a dose-dependent fashion, and a light-to-moderate consumption indeed has protective effects on cardiovascular risk factors and promotes anti-inflammatory and anti-oxidative processes. In the elderly on such a regimen, several epidemiological studies have reported a decreased risk of both coronary and cerebrovascular disease and of dementia. However, because of data heterogeneity and the presence of several confounding variables, further studies are needed to clarify these findings. In addition, the complexity of alcohol neurobiology (interaction of alcohol effects with genetic predisposition and environmental factors) and the occurrence of age-related changes should also be taken into account. As dementia, stroke and cardiovascular disease are the leading causes of mortality in older people in developed countries, a better knowledge of the mechanisms underlying the effects of alcohol intake may be helpful from the perspective not only of medical management but also of social health policy.     

Central modulatory effects of tachykinin peptides on airway tone

Previous studies suggest that structures within 1 mm of the ventral surface of the medulla (VMS) are involved in the regulation of airway resistance. Furthermore, neurons containing tachykinin peptides have been observed near the surface of the VMS. In the present work, we examined the effects of mammalian tachykinins, substance P (SP) and neurokinin A (NKA), applied locally to the intermediate area of the VMS of cats on tracheal tone and phrenic nerve activity. Since neutral endopeptidase (enkephalinase) has been shown to degrade tachykinin peptides in other tissues, we also investigated the effect of the neutral endopeptidase (NEP) inhibitors (thiorphan and phosphoramidon) on airway tone and phrenic nerve responses to tachykinins when the animals were ventilated with 100% O2 and during hyperoxic hypercapnia and isocapnic hypoxia. Experiments were performed in chloralose-anesthetized cats hyperventilated to phrenic neural apnea or so that the end tidal CO2 was just above the apneic threshold. Trachealis smooth muscle tension was assessed by measuring changes in pressure in a balloon placed in a bypassed segment of trachea (Ptseg). Application to the VMS of SP (10(-5)-10(-3) M) significantly increased tracheal muscle tension. Similar effects were found with applications of NKA. In addition, thiorphan and phosphoramidon potentiated the effects of tachykinins and the responses to hypercapnia and hypoxia of tracheal tone and phrenic nerve activity. Pretreatment with atropine (1 mg/kg) blocked tracheal but not phrenic responses to tachykinins. These suggest that (1) tachykinins acting on structures located on the VMS can increase cholinergic outflow to the airways and augment respiratory motor output, and (2) NEP may be one important modulator of tachykinin-induced effects.     

Androgen effects on cognition: congenital adrenal hyperplasia

Cognitive studies of congenital adrenal hyperplasia (CAH) patients have revealed (1) the presence of an IQ advantage in patients, siblings and parents due to socioeconomic status, genetic, hormonal, or other factors; (2) an IQ disadvantage in salt wasters compared with simple virilizers, probably due to early brain damage secondary to salt-wasting crisis; (3) a possibly increased incidence of learning disabilities, particularly in female patients and particularly for calculation abilities, due to disease-related early androgen exposure; and (4) a possible post-pubertal spatial advantage in CAH women, also due to early androgen exposure.     

The effects of oxytocin on social cognition in borderline personality disorder

Introduction

Deficits in social cognition and interpersonal difficulties are key features in borderline personality disorder. Social cognition refers to the function of perceiving and adequately dealing with social signals, leading to the establishment and maintenance of healthy and positive social relationships. Evidence suggests that oxytocin (OT) may improve social cognition and human social behavior. Recently, several studies have highlighted the beneficial effects of oxytocin in several psychiatric conditions involving social cognition deficits such as schizophrenia, autism or social phobia. However, despite growing interest, the effects of oxytocin in patients with borderline personality disorder are far from being clearly demonstrated.