Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

OBJECTIVE: Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. METHODS: Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. RESULTS: The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). CONCLUSIONS: This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

Istradefylline effects on tremor dominance (TD) and postural instability and gait difficulty (PIGD).

Background: In patients with Parkinson's Disease (PD), two distinct motor subtypes, tremor dominant (TD) and postural instability and gait difficulty (PIGD), can be differentiated using Unified Parkinson's Disease Rating Scale (UPDRS) sub-scores. This post hoc analysis of pooled data from eight pivotal studies examined the effect of treatment with istradefylline, a selective adenosine A2A receptor antagonist, on these subtypes. Methods: In eight randomized, placebo-controlled phase 2b/3 trials, patients on levodopa with carbidopa/benserazide experiencing motor complications received istradefylline (20 or 40 mg/day) or placebo for 12 or 16 weeks. TD subtype was defined by the UPDRS II/III items kinetic and postural tremor in right/left hand and (resting) tremor in the face, lips, chin, hands, or feet; PIGD items were freezing, walking, posture, gait, and postural instability. The ratio of mean scores from TD:PIGD items determined subtype (TD [TD:PIGD ratio ≥ 1.5], PIGD [TD:PIGD ratio ≤ 1.0], mixed-type [ratio 1-1.5]). Results: In total, 2719 patients were included (PIGD, n = 2165; TD, n = 118; mixed-type, n = 188; not evaluable, n = 248). Among TD subtype patients, the least-squares mean change from baseline versus placebo in UPDRS II/III TD-related total score was significant at 20 mg/day istradefylline (-2.21; 95 % CI, -4.05 to -0.36; p = 0.02). For PIGD subtype patients, there was a significant difference from placebo in UPDRS II/III PIGD-related total score at 40 mg/day istradefylline (-0.25; -0.43 to -0.06; p = 0.01). Conclusions: The data from this analysis of UPDRS-based motor subtypes suggest that istradefylline can improve motor disability in PD patients with motor fluctuations regardless of PD subtype. Future research should characterize the effects of istradefylline on tremor.

How and why the adenosine A2A receptor became a target for Parkinson's disease therapy.

Dopaminergic therapy for Parkinson's disease has revolutionised the treatment of the motor symptoms of the illness. However, it does not alleviate all components of the motor deficits and has only limited effects on non-motor symptoms. For this reason, alternative non-dopaminergic approaches to treatment have been sought and the adenosine A2A receptor provided a novel target for symptomatic therapy both within the basal ganglia and elsewhere in the brain. Despite an impressive preclinical profile that would indicate a clear role for adenosine A2A antagonists in the treatment of Parkinson's disease, the road to clinical use has been long and full of difficulties. Some aspects of the drugs preclinical profile have not translated into clinical effectiveness and not all the clinical studies undertaken have had a positive outcome. The reasons for this will be explored and suggestions made for the further development of this drug class in the treatment of Parkinson's disease. However, one adenosine A2A antagonist, namely istradefylline has been introduced successfully for the treatment of late-stage Parkinson's disease in two major areas of the world and has become a commercial success through offering the first non-dopaminergic approach to the treatment of unmet need to be introduced in several decades.

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson's Disease.

The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson's disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.

Efficacy and safety of istradefylline in patients with Parkinson's disease presenting with postural abnormalities: Results from a multicenter, prospective, and open-label exploratory study in Japan.

Postural abnormalities in Parkinson's disease (PD) can devastatingly impair the quality of life, especially in patients with advanced disease, and are generally refractory to dopaminergic agents. The objective of this exploratory study was to investigate the efficacy and safety of istradefylline for the treatment of postural abnormalities in PD. In this open-label, 24-week, single-arm prospective trial, PD patients with postural abnormalities experiencing the wearing-off phenomenon on levodopa-containing therapies were enrolled and received a starting dose of 20 mg/day istradefylline orally for 4 weeks, which was then increased to 40 mg/day. The primary endpoint was the change from baseline to week 24 in the 14-item Unified Dystonia Rating Scale (UDRS) total score. Pivotal secondary endpoints were changes in the sub-items of UDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, and adverse drug reactions (ADRs). Overall, 24/31 enrolled patients completed the study; mean (standard deviation) age and duration of motor complications were 73.3 (7.7) years and 3.2 (4.4) years, respectively. Mean (95% confidence interval [CI]) change in the UDRS total score was 4.84 (1.97, 7.71; P = 0.002), with significant improvements in the neck, right distal arm and hand, and trunk severity scores. Mean (95% CI) change in the MDS-UPDRS part III score was 7.84 (4.34, 11.34; P < 0.001). The most common ADRs were malaise, dyskinesia exacerbation, and visual hallucinations in 2 (6.5%) patients each. This exploratory study demonstrated that istradefylline could be efficacious for postural abnormalities and was generally well tolerated in patients with PD experiencing the wearing-off phenomenon with levodopa-containing therapies.

Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson's Disease: A Pooled Analysis of 8 Phase 2b/3 Trials.

BACKGROUND: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson's disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. OBJECTIVE: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. METHODS: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline's FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. RESULTS: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], -0.38 h [-0.61, -0.15]) and 40 mg/day (-0.45 h [-0.68, -0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, -0.75 h [-1.10, -0.40]; 40 mg/day, -0.82 h [-1.17, -0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). CONCLUSION: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

How Are Adenosine and Adenosine A2A Receptors Involved in the Pathophysiology of Amyotrophic Lateral Sclerosis?

Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson's disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy.

Istradefylline - a first generation adenosine A2A antagonist for the treatment of Parkinson's disease.

Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of PD.Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A2A antagonist currently in clinical use.Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.

How do adenosine A2A receptors regulate motor function?

Adenosine A2A receptor antagonism is a new therapeutic strategy in the symptomatic treatment of Parkinson's disease (PD). This review addresses how adenosine A2A receptors are involved with the control of motor function via the basal ganglia-thalamocortical circuit, and considers the anatomical localization and physiological function of the receptor, along with its ultrastructural localization in critical areas/neurons of the circuit. Based on this understanding of the functional significance of the adenosine A2A receptor in the basal ganglia, the mode of action of A2A receptor antagonists is explored in terms of the dynamic functioning of the basal ganglia and the activity of the internal circuits of the striatum in PD. Finally, the pathophysiological differences between the normal and PD states are examined to emphasize the importance of the adenosine A2A receptor.

Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?

Treatment of non-motor symptoms of Parkinson's disease (PD) is a major unmet need. Targeting adenosine A2A receptors may address some of the neuropsychiatric components of non-motor symptoms - notably cognitive impairment, depression and excessive daytime sleepiness. A2A receptors are located primarily on the indirect gamma-aminobutyric acid (GABA)-ergic striatal output pathway but are also present to some extent in limbic areas of the brain, particularly the nucleus accumbens. Extensive studies show that adenosine antagonists are effective in reversing cognitive deficits in a range of experimental models related to the early executive and visuo-spatial deficits seen in PD. Similarly, A2A receptor antagonists can reverse depressive symptoms in experimental models of PD, including models with high predictive value of effect in humans, and to the same extent as classical antidepressants. Importantly, A2A antagonists are effective in models of the motivational symptoms of depression, which may relate to the apathetic/anhedonic expression of depression that can occur in PD. Adenosine and A2A receptors play a prominent role in regulating the sleep-wake cycle with arousal attributed to A2A receptor antagonism. In rodents, A2A receptor antagonists appear to induce arousal in the active part of the daily cycle only, and not during the inactive phase. This was suggested in small clinical studies in PD where A2A antagonism improved daytime sleepiness without impairing nocturnal sleep. In conclusion, A2A antagonists have potential to affect a range of neuropsychiatric components of PD; this clinical potential requires further investigation in humans.

A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease.

BACKGROUND: Characterization of patient factors associated with istradefylline efficacy may facilitate personally optimized treatment. OBJECTIVES: We aimed to examine which patient factors are associated with favorable istradefylline treatment outcomes in PD patients with motor complications. METHODS: We performed a pooled analysis of data from two identical phase 2b and 3 Japanese studies of istradefylline. Logistic regression models were used to assess the association of 12 patient characteristics with favorable outcomes. RESULTS: Off time reduction and increased good on time with istradefylline provided a significantly favorable response in patients aged ≥65 years. Off time reduction was more favorable in patients with ≥8-hour daily off time at baseline. Improvement in UPDRS Part III was favorable in patients with UPDRS Part III baseline score ≥ 20. CONCLUSIONS: Several patient factors influenced the effect of istradefylline on motor fluctuations, motor function, activities of daily living, and clinical impression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Safety and effectiveness of istradefylline in patients with Parkinson's disease: interim analysis of a post-marketing surveillance study in Japan.

BACKGROUND: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A2A receptor antagonist for the treatment of Parkinson's disease (PD) in patients experiencing the wearing-off phenomenon with levodopa (L-DOPA). The authors present an interim report from a post-marketing surveillance (PMS) evaluating the safety and effectiveness of long-term istradefylline in a real-world setting. RESEARCH DESIGN AND METHODS: Istradefylline safety was assessed by the incidence of adverse events (AE) and adverse drug reactions (ADRs). Effectiveness was assessed using the physician's assessment of off-time, off-time symptoms and motor dysfunction, unified PD rating scale (UPDRS) Part III score, and the physician's global assessment. RESULTS: This analysis evaluated 476 patients. Istradefylline was generally well tolerated, despite dyskinesia and hallucination being the most common ADRs. Reduction in off-time was observed in 38.2% of patients, off-time symptoms were improved or markedly improved in 44.7%, and motor dysfunction was improved or markedly improved in 48.5%. The mean UPDRS Part III score decreased from 33.7 to 30.3 at the end of the study. The physician's global assessment rated the drug as effective in 61.3% of patients. CONCLUSIONS: This PMS provides useful safety and effectiveness data for long-term treatment with istradefylline in a real-world setting for patients with PD exhibiting the wearing-off phenomenon with L-DOPA.

The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets.

The adenosine A2A receptor antagonist, istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of L-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of istradefylline on motor function when administered in combination with low dose of L-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of L-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Threshold doses of ropinirole (0.025-0.075 mg/kg p.o.) and pergolide (0.01 mg/kg p.o.) produced a weak anti-parkinsonian effect. Co-administration of a suboptimal dose of L-DOPA (2.5mg/kg p.o.) with threshold doses of the dopamine agonists enhanced their anti-parkinsonian effect that led to increased 'ON' time without dyskinesia appearing. Administering istradefylline (10mg/kg p.o.) with the threshold doses of dopamine agonists and the suboptimal dose of L-DOPA in a triple combination caused a further enhancement of the anti-parkinsonian response but dyskinesia was still absent. In early PD, dopamine agonists are often used as first-line monotherapy, but efficacy is usually lost within a few years, at which time L-DOPA is added but with the risk of dyskinesia appearance. These results show that istradefylline is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia.

Revisiting the extended producer responsibility program for metal packaging in South Korea.

Recently, developed and emerging countries have increasingly adopted the principle of extended producer responsibility (EPR) to reduce waste. In 2003, South Korea replaced the waste deposit recycling (WDR) program with the EPR program. Previous comparative analyses between the WDR and EPR programs have been qualitative evaluations and have not yet quantitatively shown whether the change has increased benefits. The aim of this paper is to explore which program brings larger net benefits. Because of limited data availability, here we focus on metal packaging exclusively. We find that the recycling rate dropped from 59% in 2000 to 40% in 2011 and recycling volume dropped accordingly. Cost-benefit incidence analysis shows that net social benefits decreased by 2.8 billion won (2.5 million US dollars), while the net benefits to producers increased by 1.9 billion won (1.7 million US dollars) under the EPR program compared with the WDR program. The government of South Korea should set an ambitious recycling target and narrow the scope of the exemption from the mandatory recycling requirement.

The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets.

The adenosine A2A receptor antagonist, istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged 'OFF' periods. In contrast, the effects of istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01-0.1mg/kg p.o.) and pergolide (0.003-0.1mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025-0.075mg/kg p.o.) and pergolide (0.01-0.075mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of istradefylline (10mg/kg p.o.) alone resulted in a decrease in motor disability and increase in 'ON' time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with istradefylline resulted in an increase in the reversal of motor disability and increase in 'ON' time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that istradefylline is effective in improving motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting.

Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson's disease.

Adenosine A2A receptor antagonists are classified to be a recent new therapeutic strategy for the symptomatic treatment of Parkinson's disease, a hypokinetic movement disorder. First, this chapter addresses how adenosine A2A receptors are involved with brain motor control via the basal ganglia-thalamocortical circuit, considering anatomical and ultrastructural localization of the receptor in critical areas/neurons of the circuit. Then, based on the understanding of the functional significance of the receptor in the circuit, the mode of action of adenosine A2A receptor antagonists is explained by dynamism of the circuit and possible cellular mechanisms, highlighting the importance of the pathophysiological difference proposed between normal and disease state.

Adenosine A2A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets.

The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson's disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with sub-maximal doses of L-DOPA. However, the effects of combining istradefylline with sub-optimal L-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to L-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of L-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with L-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of L-DOPA in the treatment of Parkinson's disease without causing or worsening dyskinesia.

Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats.

RATIONALE: Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. OBJECTIVE: We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. RESULTS: Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the ß-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. CONCLUSIONS: Istradefylline exerts antidepressant-like effects via modulation of A2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.

Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents.

RATIONALE: Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. OBJECTIVE: We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. RESULTS: Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. CONCLUSIONS: Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic-pituitary-adrenal axis.