Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications.

BACKGROUND: The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits. METHODS: Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed. RESULTS: Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits. CONCLUSION: Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits.

Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study.

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 µg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 µg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 µg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.

Effects of experimental panic on neuroimmunological functioning.

OBJECTIVE: Psychoimmunological research in panic disorder (PD) so far focussed on single time point evaluation in resting conditions. No robust evidence for changes in the immune system was found using this method. However, PD is characterized by the occurrence of unexpected panic attacks (PAs). The current research focuses on cytokine and acute phase protein (APP) levels and mitogen-induced cytokine secretion following 35% CO(2) inhalation-induced panic. METHODS: Eighteen PD patients and 18 matched healthy control subjects underwent both a placebo and a 35% CO(2) inhalation on separate days. Blood samples for cytokine and APP determination were taken before and after the inhalation. In addition to serum determination, whole blood samples were cultured and stimulated with mitogens for assessment of the functional capacity of the immune system. RESULTS: The 35% CO(2) inhalation induced significantly higher levels of anxiety in PD patients as compared to the control subjects, but no differences in immune parameters were found, either in basal conditions or after experimental panic induction. CONCLUSION: In our sample we do not find any changes in serum levels or functional capacity of several immunological parameters in the experimentally provoked PAs. Similar results have been found in social phobia, whereas in other affective disorders such as depression and posttraumatic stress disorder, immune changes are evident. Changes seem to coincide with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, the bidirectional communication pathway between the immune system and the HPA axis might play a role in some affective disorders, but it does not specifically seem to be involved in the etiology of PD.

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial.

INTRODUCTION: Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating. METHODS: The current study investigated the effects of the PDE4 inhibitor roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 µg). RESULTS: Results show that roflumilast improves sensory gating in healthy young human volunteers only at the 100-µg dose. The effective dose of 100 µg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study. CONCLUSION: The PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

CO2 challenge results in hypothalamic-pituitary-adrenal activation in healthy volunteers.

The 35% CO(2) challenge is known to induce symptoms of a panic attack both in panic disorder (PD) patients and healthy volunteers. Although the challenge applies more to PD patients, studies in healthy volunteers provide the opportunity to isolate the physical symptoms from the disorder and to focus on the direct effect from the challenge on stress responsive systems. One of the main stress responsive systems is the hypothalamic-pituitary-adrenal (HPA) axis. It remains unclear whether panic symptoms are accompanied by HPA axis activation. Differences in design have hampered any comparison between studies. For example, both serum and salivary cortisol have been used to provide an index of HPA axis activation. Furthermore, indications for central HPA axis disturbance have been suggested. The current study aimed to study the HPA axis response following the induction of panic symptoms in healthy volunteers, both at the pituitary level and at the adrenal level. Furthermore, both serum and salivary cortisol levels were determined. Subjective feelings of anxiety and, correspondingly, cortisol and ACTH levels, were found to be significantly increased following the 35% CO(2) challenge. Cortisol and ACTH responses to CO(2) were also associated. A significant cortisol increase was observed in both serum and saliva samples, although these were more pronounced when considering the free fraction serum values. We conclude that the induction of panic symptoms results in HPA axis activation, both at the pituitary and adrenal level. The question remains as to whether positive responders to the 35% CO(2) inhalation (more specifically PD patients) show a more pronounced HPA axis response.

Hypothalamic-pituitary-adrenal axis function following a 35% CO2 inhalation in healthy volunteers.

RATIONALE: The hypothalamic-pituitary-adrenal axis (HPA axis) is a central component of the brain's neuroendocrine response to stress. The extent of increase in cortisol secretion, provides an index of the HPA axis activity, and in this way, objectively reflects perceived stress. In healthy subjects, the 35% CO(2) inhalation does hardly induce stress, as expressed in anxiety. However, inconsistent results have been found in studies investigating the cortisol response following CO(2) inhalation. Clarity has to be reached about the normal reaction to this challenge, especially because this model is still a very valuable method to study central aspects of panic. OBJECTIVES: The present study aimed to test the hypothesis that a single breath of 35% CO(2) would not induce cortisol release in healthy volunteers. METHODS: In the current study, 20 healthy subjects underwent both a 35% CO(2) and a placebo inhalation in a randomised, single blind fashion. Cortisol levels were determined in saliva samples, taken at regular intervals. RESULTS: No differences were found between the CO(2) and the placebo condition. In both conditions a significant time effect was found, which can be subscribed to normal variation in the circadian rhythm. Furthermore, only modest subjective anxiety scores were found in the CO(2) condition. CONCLUSIONS: These results provide biological evidence for the hypothesis that healthy subjects are not affected by the 35% CO(2) challenge in a clinically significant way. Characteristic, PD patients react much stronger to the inhalation. Thus, in addition to psychological parameters, healthy subjects also constitute an ideal comparison group with regard to endocrinological parameters.

Salivary cortisol in panic: are males more vulnerable?

OBJECTIVES: The underlying mechanisms of panic attacks (PA's) are still unclear. Theories focusing on these mechanisms differ in their description of the relationship between panic and fear. The main controversy concerns whether a PA resembles the classical flight response, or whether it is qualitatively different from fear. According to the first theory, a PA would result in hypothalamic-pituitary-adrenal axis (HPA-axis) activation, whereas according to the second, it would not. So far, inconclusive results have been reported in studies measuring HPA-axis activity after laboratory evoked PA's. The present study was designed to assess cortisol levels following a 35% CO2 challenge in Panic Disorder (PD) patients compared to healthy volunteers as a measurement of HPA-axis activity. DESIGN: Twenty-three PD patients and 20 healthy volunteers participated in the study. Cortisol was determined in saliva at regular intervals before and after the challenge. Furthermore, attention was paid to possible gender effects. RESULTS: Although the 35% CO2 inhalation induced a significant increase in anxiety, no cortisol increase was found. Moreover, there was no difference between patient and control cortisol values following the 35% CO2 challenge, whereas the delta anxiety scores were far more pronounced in the patient group. Interestingly, male PD patients showed higher cortisol values. CONCLUSIONS: This study may be in accordance with the view that PA's are not accompanied by an important HPA-axis activation. There are some indications for aberrant cortisol secretion in male PD patients. Further research needs to confirm whether male and female PD patients differ in their underlying mechanisms related to HPA-axis activity.

Objective and subjective measures in recovery from a 35% carbon dioxide challenge.

OBJECTIVES: Because hyperventilation, dyspnea, and a feeling of choking are often core features of a panic attack, respiration has been one of the most widely studied physiological parameters in panic disorder (PD) patients. A respiratory subgroup of PD, with distinct etiological pathways, has also been suggested. Investigation of the recovery phase following a respiratory challenge may be a reliable way to establish respiratory impairment in PD patients. The objective of the present study was to investigate the recovery phase from a 35% carbon dioxide challenge in PD patients and in healthy controls, and to test the hypothesis of a different respiratory pattern in patients, compared to control subjects. METHODS: Eleven nonmedicated PD patients with or without agoraphobia, 11 medicated PD patients, and 11 control subjects took part in a 35% carbon dioxide and 65% oxygen inhalation challenge. Respiratory rate, partial pressure of carbon dioxide, heart rate, and blood pressure were recorded during the baseline phase (10 minutes) and the recovery phase (10 minutes). Visual Analogue Scale of Anxiety and Panic Symptom List scores were collected pre- and post-challenge. RESULTS: Nonmedicated patients had increased variability in respiratory rate and partial pressure of carbon dioxide during recovery, compared with control subjects and medicated PD patients. Also, PD patients tended to have higher heart rates and to need more time to recover from the challenge than control subjects. CONCLUSIONS: Results suggest that PD patients have less effective homeostatic control after their physiological equilibrium has been disrupted by a respiratory stressor.

CO2 challenge induced HPA axis activation in panic.

The hypothalamic-pituitary-adrenal axis (HPA axis) plays a critical role in stress management. Involvement of this physiological axis in the underlying mechanisms of panic disorder (PD) has been suggested. Studies using 35% CO(2) inhalation to provoke panic found no evidence for robust increases in cortisol levels in PD. However, cortisol levels alone may not be conclusive, as this hormone is merely the end product of a complex physiological axis. Sixteen PD patients and 16 healthy control subjects underwent a 35% CO(2) inhalation and a placebo inhalation on separate days according to a fixed order, double-blind design. Both serum and salivary cortisol, as well as adrenocorticotropic hormone (ACTH) were measured at regular time intervals. Cortisol and ACTH levels increased in the patient and control groups following 35% CO(2) inhalation. The magnitude of the increase was similar in patients and controls despite marked differences in anxiety. This study is the first to document a clear HPA response following 35% CO(2) inhalation in both PD patients and controls. This effect occurs independently of the specific panicogenic properties of the CO(2) challenge. It remains to be clarified whether panic is initially accompanied by major HPA axis activation or whether other stress-responsive systems underlie panic.