Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults.

The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 µg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 µg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

The PDE5 inhibitor vardenafil does not affect auditory sensory gating in rats and humans.

RATIONALE: Sensory gating is an adaptive mechanism of the brain to prevent overstimulation. Patients suffering from clinical disorders such as Alzheimer's disease or schizophrenia exhibit a deficit in gating, which indicates not only an impairment in basic information processing that might contribute to the cognitive problems seen in these patients. Phosphodiesterase type 5 inhibitors (PDE5-Is) have been shown to improve cognition in rodents in various behavioural tasks and might consequently be an interesting target for cognition enhancement. However, the effects of PDE5-Is on sensory gating are not known yet. OBJECTIVES: This work aims to study the effects of PDE5 inhibition on auditory sensory gating in rats and humans. METHODS: In the rat study, vehicle or 0.3-3 mg/kg of the PDE5-I vardenafil was given orally 30 min before testing and electrode locations were the vertex, hippocampus and the striatum. The human subjects received placebo, 10-20 mg vardenafil 85 min before testing and sensory gating was measured at the cortex (Fz, Fcz and Cz) electrodes. RESULTS: Significant gating was only found for the N1 component in rats while all three peaks P1, N1 and P2 showed gating in humans, i.e. the response to the second sound click was decreased as compared with the first for these deflections. Administration of vardenafil did neither have an effect on sensory gating in rats nor in humans. CONCLUSIONS: These findings imply that positive effects of PDE5 inhibition on cognition are not mediated by more early phases of information processing.

Challenging anxiety: a focus on the specificity of respiratory symptoms.

Physiological symptoms are characteristic features of anxiety states. Presumably, specific psychophysiological profiles differentiate between anxiety disorders, which would offer potential for diagnostic purposes. Abundant evidence points to a causal relationship between panic disorder and instability of respiratory regulation. However, the specificity of most measures that indicate aberrant functioning of the respiratory system in PD can be questioned. Possibly, the traditional measures of respiratory functioning are too restricted. The underlying respiratory vulnerability in PD seems to constitute a subtle, unstable trait, which calls for more sensitive and sophisticated measures of respiratory variability and chaos. To increase the probability of finding parameters with diagnostic specificity, the application of disorder specific challenge paradigms is recommended.

Desynchrony of fear in phobic exposure.

Intuitively, phobic exposure would seem to be a very stressful experience. However, it is not clear whether the characteristic feature of a classic stress response, activation of the hypothalamic-pituitary-adrenal (HPA) axis, is present in phobic fear. Some instances of phobic fear have been found to be accompanied by robust increases in cortisol, whereas in other instances a dissociation between subjective-behavioural arousal and the HPA-axis has been found. The latter is referred to as desynchrony of fear. The aim of the current study was to test the hypothesis that phobic fear is similar to normal fear and, as such, is accompanied by a robust increase in cortisol values. In all, 16 spider phobic subjects and 16 healthy controls participated in the study. During and following a standardised stepwise exposure paradigm, saliva samples were collected for cortisol determination. In contrast to the controls, the spider phobics reacted with a strong fear reaction to the spiders. However, cortisol levels remained unaffected. The phobic response did not resemble the classic 'fight or flight' response. Some suggest that the HPA-axis response has become extinguished in modern man. Yet, it is possible that phobic fear is not a derivative of an ancient fear but rather a separate entity that relies on other neuroendocrinological systems.

Respiratory patterns in panic disorder reviewed: a focus on biological challenge tests.

OBJECTIVE: To provide a systematic review of studies investigating respiration in PD and comments on relative inconsistencies. METHOD: A Medline search of controlled studies focusing on pCO(2), respiratory rate, tidal volume, and minute volume in PD patients was conducted for baseline/resting condition, challenge, and recovery phase. Respiratory variability and comparisons between panickers and non-panickers were also examined. RESULTS: Lower pCO(2) levels in PD subjects are a consistent finding during the baseline/resting condition, the challenge, and recovery phases. Tidal volume and minute volume are increased in PD subjects relative to controls during the baseline/resting condition. However, the most robust finding is a higher than normal respiratory variability, which appears to be a promising factor for the identification of respiratory etiopathological pathways in PD. CONCLUSION: Respiratory variability might be a candidate for a biological marker of PD: an abnormal breathing pattern as found in panic disorder (PD) patients compared with controls might indicate instability of the respiratory homeostasis.

Neuroimmunological parameters in panic disorder.

BACKGROUND: The interaction between immune cells, neurotransmitters and the neuroendocrinological systems plays a role in affective disorders, especially depression. Although panic disorder (PD) shares a lot of features with depression, it is clearly a distinct disorder. Reports on immunological parameters in PD don't provide a clear picture of the immunological status of PD patients. This can partly be attributed to methodological differences between studies and small patient groups. OBJECTIVE: The present study aims to assemble all studies on immunological parameters in PD in order to combine all available data to gain a broader perspective on this matter. METHOD: PubMed was searched for studies describing immunological parameters in PD patients without comorbid disorders or medication use. All studies had to include a healthy control group and the outcome measures had to be shared by at least one other study. RESULTS: Fourteen articles were found. Although the T-lymphocytic branch and the innate immune system were normal, the B-lymphocytic branch showed some differences between PD patients and healthy controls. B-cell counts were increased in PD patients, which was underlined by increased human leucocyte antigen (HLA)-DR counts and increased immunoglobulin A levels. However, B-cell activity following mitogen stimulation was normal. CONCLUSIONS: PD patients show increased B-cell numbers. The finding that B-cell activity is not increased can possibly be attributed to functional exhaustion of these cells. The meaning of this finding remains unclear, although it may be potentially important in affective disorders as the same has been found in depression.

Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies.

OBJECTIVES: Serotonin (5-hydroxytryptamine; 5-HT) and endocrine abnormalities have been repeatedly reported in bipolar disorders (BD). Useful methods to investigate 5-HT responsivity, and the interaction with neuroendocrine functioning, are provided by acute 5-HT challenge and depletion paradigms. In this review 5-HT challenges are limited to paradigms that stimulate 5-HT activity in BD. METHODS: Literature was searched for in electronic libraries: MEDLINE and PSYCHLIT, period 1966-2001. Papers describing effects of an acute 5-HT challenge on neuroendocrine functioning in BD patients were selected. RESULTS: Review of the literature revealed 15 studies: five papers described the effects of 5-HT challenges in manic BD patients, four papers in euthymic BD and seven in depressed BD patients. The reviewed 5-HT challenge paradigms are acute administration of oral and intravenous (i.v.) dosage of d,l-fenfluramine, tryptophan, 5-hydroxytryptophan, ipsapirone and buspirone. There were no papers which investigated neuroendocrine effects of m-chlorophenylpiperazine, clomipramine and citalopram in BD patients and were therefore not reviewed. CONCLUSIONS: The literature on 5-HT challenge procedures in BD shows evidence for a blunted prolactin (PRL) in mania and depression as well as a blunted cortisol in euthymic BD patients. This suggests that in both mania and depression similar changes in the 5-HT system are involved. It is speculated that blunting of cortisol responses in euthymic BD patients may be a result of chronically altered 5-HT functioning, whereas changes in PRL release following 5-HT challenges reflect more state-dependent changes in 5-HT activity. The 5-HT responsivity in BD patients has also been associated with pharmacological treatment, suicidal behaviour, weight loss and age. Recommendations for future research are given.