Wim J. Riedel

The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women : A meta-analysis

We reviewed epidemiological and experimental studies of female gonadal hormone replacement therapy (HRT) on cognitive function in post-menopausal women and carried out meta-analyses. In healthy ageing women, HRT has small and inconsistent effects that include enhancement of verbal memory, abstract reasoning and information processing. Epidemiological studies show larger effects than experimental studies, which is not related to sample size. Important confounds may be that women who start using HRT are healthier than women who do not. Also, controlling for socio-economic status diminishes the effect of HRT. The effects of HRT may depend on the age and type of menopause and the therapeutic intervention used, with the most widely used drug, Premarin, having least effect. However, the effects are independent of mood and climacteric symptom alleviation. There is a paucity of experimental studies that include healthy elderly women. The evidence for an estrogen deficiency in women with dementia and cognitive dysfunction is inconsistent. Nevertheless, epidemiological studies suggest that HRT protects against the development of clinically diagnosed Alzheimers disease. However, poor recall of HRT use by patients and altered physician behaviour may have confounded the effects. Surprisingly, both healthy and demented women with low education seem to benefit most from HRT. Three recent controlled experimental studies using Premarin showed no effects of HRT in preventing further cognitive decline in women who already have Alzheimers disease. Duration of treatment seems to play an important role, with beneficial effects declining-and even reversing-with longer treatment in women with Alzheimers disease.Future research should further investigate the cognitive effect of different HRT preparations, serum estrogen levels, and the interactions of HRT with age, menopausal status and existing protective (e.g. education) and risk factors (e.g. smoking and apolipoprotein E genotype) for cognitive decline and Alzheimers disease.

Cognitive impairment in depression: a systematic review and meta-analysis

BACKGROUND This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. METHOD We conducted a systematic review and meta-analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. RESULTS Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohens d effect sizes ranging from -0.34 to -0.65). Significant moderate deficits in executive function and attention (Cohens d ranging from -0.52 to -0.61) and non-significant small/moderate deficits in memory (Cohens d ranging from -0.22 to -0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. CONCLUSIONS Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions.

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs.

Cognitive performance after strenuous physical exercise

Stimulating as well as detrimental effects of exercise on cognitive functioning have been reported. In the present study, 15 endurance-trained athletes (aged 18 to 42 years) performed a bicycle ergometer endurance test at 75% of their maximal work capacity (Wmax). Psychomotor and cognitive tests were administered before and immediately after exercise. These consisted of simple reaction time (RT), 3-choice RT and Stimulus-Response (S-R) incompatible RT tasks, a finger-tapping task, and the Stroop test. Simple RT tasks, but also the more complex S-R in compatible RT, and Color Word Interference in the Stroop test showed an increase in speed of performance after exercise relative to baseline. An enhanced activation was probably responsible for this better performance on psychomotor and cognitive tests. Since performance on the most complex task, the Interference subtest of the Stroop, was especially improved after exercise, the expectancy of the subjects of a potential positive effect of exercise was thought to have been responsible.

Serotonin and human cognitive performance.

In the past decade, experimental studies involving healthy human volunteers have revealed that manipulations of the central serotonin (5-HT) system can produce quite specific changes in cognitive functioning, independent of overt mood changes. Reduced 5-HT turnover is consistently associated with impaired long-term memory functioning. Low 5-HT function may also impair cognitive flexibility and improve focused attention. On the other hand, stimulation of central 5-HT has repeatedly been found to impair performance in a true vigilance task. Currently, there is little evidence for mirrored cognitive changes due to opposite 5-HT manipulations in healthy volunteers. Given the mounting evidence for a role of 5-HT in human cognition, reduced 5-HT function could be directly linked to cognitive disturbances in certain conditions, such as in depression and Alzheimers Disease (AD). There is evidence that stimulating (i.e. normalizing) 5-HT activity in depression may have specific beneficial effects on cognition, independent of a general relief of depressive symptoms, but this premise needs to be confirmed by larger-scale clinical studies. Recently, a potential role of 5-HT in the cognitive symptoms in AD has been identified, but there is insufficient data to evaluate the effects of 5-HT stimulation on cognitive symptoms in AD. It is concluded that serotonin is a potential target for pharmacological cognition enhancement, particularly for restoration of impaired cognitive performance due to 5-HT dysfunction. Further differentiation of the role of 5-HT in normal and disturbed cognition and evaluation of the effects of 5-HT manipulations in various populations is required to establish the full potential of 5-HT drugs as cognition enhancers.

Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders

BACKGROUND Acute tryptophan (TRP) depletion was evaluated in healthy volunteers with or without a family history of major affective disorder (FH+ versus FH-). METHODS Twenty-seven subjects (16 FH+, 11 FH-) received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind cross-over design and a diet devoid of TRP for the next 24 hours. RESULTS The ratio TRP/large neutral amino acids declined to 22% of baseline values after 6 hours, and increased during the night reaching 85% of baseline after 24 hours. Overall, after 6 hours, TRP depletion lead to a lowering of mood, but after 24 hours, these changes were no longer detected. Mood changes and gastrointestinal side effects were significantly more evident in FH+ subjects than in FH- subjects. CONCLUSIONS Our data support the hypothesis that subjects with a positive family history for depression are predisposed to increased vulnerability to the adverse consequences of serotonergic imbalance.

Effects of acute tryptophan depletion on memory, attention and executive functions: A systematic review

The serotonergic system is implicated in the regulation of mood and cognition. Acute tryptophan depletion (ATD) is an experimental procedure for lowering central serotonin levels. Here, the effects of ATD on psychomotor processing, declarative memory, working memory, executive functions and attention are discussed. The most robust finding is that ATD impairs the consolidation of episodic memory for verbal information. Semantic memory appears to be unaffected by ATD although a limited variety of tasks examined effects in this domain. Similarly, evidence suggests ATD does not influence verbal, spatial and affective working memory. Most studies investigating effects on executive functions have produced non-specific or negative findings. In terms of attention, ATD either does not affect or may improve focused attention and ATD likely does not impact sustained and divided attention or attentional set-shifting. Although ATD is known to affect mood in certain vulnerable populations, the effects of ATD on cognition in non-vulnerable participants are independent of mood changes. Suggestions for future directions and implications for psychiatric illnesses are discussed.

Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors.

The current study was carried out to investigate the cognitive effects of two serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, with special reference to differences in their affinity for other neurotransmitter systems, i.e. anticholinergic activity of paroxetine and putative dopamine reuptake activity of sertraline. The study was conducted according to a double-blind, three-way cross-over design. During three treatment periods of 2 weeks, 24 healthy middle-aged (aged 30–50 years) subjects of both sexes received sertraline (50 mg on days 1–7, 100 mg on days 8–14), paroxetine (20 mg on days 1–7, 40 mg on days 8–14) and placebo. Paroxetine specifically impaired delayed recall in a word learning test at a dose of 20 and 40 mg. Sertraline did not affect word learning but improved performance on a verbal fluency task at a dose of 50 and 100 mg. Neither drug affected performance on a short-term memory scanning task. These subtle but significant changes in cognitive performance can be explained by subtle differences in pharmacological profiles of these SSRIs. The additional anticholinergic effects of paroxetine could account for its induction of long-term memory impairment. Similarly, the additional dopaminergic effects of sertraline could account for its induction of slightly improved verbal fluency. The impairing and facilitating cognitive effects of paroxetine and sertraline, respectively, may be more pronounced in the elderly depressed patient.

Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers.

BACKGROUND Serotonergic circuits have been proposed to mediate cognitive processes, particularly learning and memory. Cognitive impairment is often seen in bipolar disorders in relation to a possible lowered serotonergic turnover. METHODS We investigated the effects of acute tryptophan depletion (ATD) on cognitive performance in healthy first-degree relatives of bipolar patients (FH) (N= 30) and matched controls (N= 15) in a placebo-controlled, double-blind cross-over design. Performance on planning, memory and attention tasks were assessed at baseline and 5 h after ATD. RESULTS Following ATD, speed of information processing on the planning task was impaired in the FH group but not in the control group. FH subjects with a bipolar disorder type I relative (FH I) showed impairments in planning and memory, independent of ATD. In all subjects, ATD impaired long-term memory performance and speed of information processing. ATD did not affect short-term memory and focused and divided attention. CONCLUSIONS The results suggest serotonergic vulnerability affecting frontal lobe areas in FH subjects, indicated by impaired planning. Biological vulnerability in FH I subjects is reflected in impaired planning and memory performance. In conclusion, the cognitive dysfunctions in FH subjects indicate an endophenotype constituting a possible biological marker in bipolar psychopathology. Serotonin appears to be involved in speed of information processing, verbal and visual memory and learning processes.

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimers disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA(A) α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.