A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders.

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 ± 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4 ± 7.3) were examined with PET after a single bolus injection of [(11)C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [(11)C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [(11)C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [(11)C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life.

Oral almotriptan vs. oral sumatriptan in the abortive treatment of migraine: a double-blind, randomized, parallel-group, optimum-dose comparison.

BACKGROUND: Almotriptan malate is a novel, selective serotonin(1B/D) agonist, or triptan, developed for the abortive treatment of migraine. In double-blind, placebo-controlled studies, it has been shown to be effective, well tolerated, and safe. OBJECTIVE: To compare the efficacy, tolerability, and safety of almotriptan with that of the "standard triptan," sumatriptan succinate. The power calculation of the study was based on 24-hour headache recurrence, an efficacy measure in the abortive treatment of migraine, and on the occurrence of adverse events. SUBJECTS AND METHODS: Subjects, aged between18 and 65 years, with migraine with or without aura but otherwise healthy, were randomized to take orally either almotriptan malate, 12.5 mg, or sumatriptan succinate, 50 mg. The medications were provided in identical-looking capsules to ensure blinding and were taken for the treatment of moderate or severe headache. Efficacy was determined in terms of (1) headache relief-a decrease in pain intensity to mild or no pain; (2) headache freedom-a decrease to no pain; (3) use of rescue medications, allowed after 2 hours; and (4) headache recurrence-moderate or severe pain returning within 24 hours after headache relief at 2 hours. Adverse events were collected for 96 hours after treatment and for safety evaluation, vital signs, blood tests, and electrocardiograms were performed at the screening and exit visits. RESULTS: Seventy-five investigators enrolled 1255 subjects of whom 1173 were treated (591 with almotriptan and 582 with sumatriptan). At 2 hours, almotriptan treatment provided headache relief in 58.0% of the subjects and sumatriptan treatment in 57.3%; headache freedom was provided by the medications in 17.9% and 24.6%, respectively (P =.005). Rescue medications were taken by 36.7% of the subjects in the almotriptan-treated group and by 33.2% in the sumatriptan-treated group; headaches returned to moderate or severe intensity in 27.4% and 24.0%, respectively. Treatment-emergent adverse events occurred in 15.2% of the subjects in the almotriptan-treated group and in 19.4% in the sumatriptan-treated group (P =.06); treatment-related adverse events occurred in 9.1% and 15.5% of the subjects, respectively (P =.001), including chest pain, which occurred in 0.3% and 2.2%, respectively (P =.004). CONCLUSIONS: Almotriptan and sumatriptan are similarly effective in the abortive treatment of moderate or severe migraine headache; they are also similarly well tolerated and safe.

Restless legs syndrome improved by pramipexole: a double-blind randomized trial.

BACKGROUND: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects. OBJECTIVE: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS. METHODS: Ten RLS patients were studied before and after two 1-month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables. RESULTS: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires. CONCLUSIONS: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition.

Treatment satisfaction, functional status, and health-related quality of life of migraine patients treated with almotriptan or sumatriptan.

BACKGROUND: Patient-reported outcomes, such as treatment satisfaction, functional status, and health-related quality of life (HRQOL) are essential components of migraine research. Almotriptan is a new selective serotonin 1B/1D agonist triptan migraine treatment. OBJECTIVE: The purpose of this double-blind, multicenter, randomized, parallel-group study was to compare treatment satisfaction, functional status, and HRQOL of patients treated with oral almotriptan versus sumatriptan, the leading triptan on the market. METHODS: Migraine patients, aged 18 to 71 years, took equivalent oral doses of 12.5 mg almotriptan or 50 mg sumatriptan for the abortive treatment of a migraine headache. Treatment satisfaction differences between study groups were assessed using a 6-item measure to determine patients' satisfaction with pain relief and satisfaction with side effects 48 hours after drug administration. Functional status was assessed by analyzing the change in patients' ability to perform normal activities during the course of the migraine. HRQOL was compared between treatment groups at 24 hours using the Migraine Quality of Life Questionnaire. End points were assessed using entries from patients' 48-hour diaries. RESULTS: A total of 1173 patients were treated with almotriptan or sumatriptan. There were no significant differences between the 2 treatment groups in terms of satisfaction with pain relief; however, patients in the almotriptan group were significantly more satisfied (less bothered) with side effects than those receiving sumatriptan (P = 0.016). Functional status and HRQOL outcomes were not significantly different between groups. CONCLUSIONS: In this study, migraine patients treated with almotriptan were significantly more satisfied with the side-effect profile of the drug than patients treated with sumatriptan. The results of this study may help inform practicing physicians and neurologists about the potential treatment satisfaction advantages of almotriptan.

Effect of estrogen and progesterone on L-dopa induced dyskinesia in MPTP-treated monkeys.

A group of 4 cynomolgus monkeys was rendered parkinsonian by the toxin MPTP and then treated daily with L-DOPA until all animals developed dyskinesia. At this point, 17 beta-estradiol, 17 alpha-estradiol and progesterone were injected s.c. singly or in combination for 7 days and the treatment with L-DOPA reinstituted. Our results show that the pretreatment with 17 beta-estradiol reduced the dyskinetic effect without altering the therapeutic response to L-DOPA, while 17 alpha-estradiol did not alter the dyskinetic and the antiparkinsonian effect.

Chronic CY 208-243 treatment of MPTP-monkeys causes regional changes of dopamine and GABAA receptors.

Four monkeys were rendered parkinsonian by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) i.v. administration and then treated chronically with increasing doses of the D1 agonist CY 208-243 (0.05, 0.1 and 0.5 mg/kg). All animals showed a dose-dependent improvement of their parkinsonian signs after the chronic CY 208-243 treatment; however, half of them developed peak-dose dyskinesias. Dopamine levels were more decreased in the striatum of MPTP-monkeys with dyskinesias compared to those without dyskinesias. [3H]SCH 23390 and [3H]SKF 38393 binding to D1 receptors were in general similar in the striatum of both groups of MPTP-monkeys except [3H]SKF 38393 binding which was lower in the posterior putamen of dyskinetic compared to non-dyskinetic monkeys reflecting decreased coupling of this receptor to G proteins. [3H]spiperone and [3H]N-n-propylnorapomorphine binding to D2 receptors in the striatum tended in general to be higher in dyskinetic compared to non-dyskinetic monkeys, and this reached statistical significance in the posterior caudate labelled with [3H]n-propylnorapomorphine. [3H]muscimol binding to GABAA receptors was significantly higher in the posterior caudate of dyskinetic compared to non-dyskinetic monkeys. The extent of striatal DA denervation, decreased D1, elevated D2 and GABAA receptors, as well as the decrease of the D1/D2 receptor ratio in the posterior striatum may be involved in the appearance of dyskinesias after chronic CY 208-243 treatment.

Effect of adding the D-1 agonist CY 208-243 to chronic bromocriptine treatment of MPTP-monkeys: regional changes of brain dopamine receptors.

1. Eleven monkeys were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): eight were treated with bromocriptine for one week and then CY 208-243 (four monkeys) or saline (four monkeys) was added to the bromocriptine treatment. 2. Addition of CY 208-243 increased the therapeutic response observed with the ergot alone without inducing dyskinesia. 3. Following MPTP, [3H]-SCH 23390 specific binding to D-1 receptors as well as [3H]-spiperone and [3H]-N-n-propylnorapomorphine specific binding to D-2 receptors increased in posterior striatum compared to control animals, whereas [3H]-SKF 38393 binding to D-1 receptors tended to decrease. 4. Dopamine receptor density was unchanged in anterior striatum of untreated MPTP-monkeys. 5. In the posterior striatum, both dopaminergic treatments decreased towards control values [3H]-SCH 23390, [3H]-spiperone and [3H]-N-n-propylnorapomorphine binding whereas they did not significantly change [3H]-SKF 38393 specific binding. [3H]-SKF 38393 specific binding increased in anterior striatum of bromocriptine-treated MPTP-monkeys, compared to untreated MPTP-animals, and this increase was abolished in animals treated with bromocriptine+CY 208-243. 6. The present study shows that in MPTP-monkeys, treated or not with DA agonists, the D1 and D2 receptor changes are concentrated in the posterior striatum and that denervation appears to cause a shift from the high to the low affinity agonist state of D1 receptors but not for the D2 subtype.

DOPA-induced "peak dose" dyskinesia: clues implicating D2 receptor-mediated mechanisms using dopaminergic agonists in MPTP monkeys.

Dopa-induced "peak dose" dyskinesia (DID) observed during the treatment of Parkinson's disease patients has traditionally been linked primarily to dopamine D1 receptor-mediated mechanisms. However, in MPTP-induced parkinsonian monkeys with DID, the administration of selective dopamine D1 or D2 agonists will, in the case of D1 agonists result in similar antiparkinsonian effect but with much less dyskinesia. Thus, once primed, enhanced D1 neural transmission might in fact benefit DID. In drug-naive MPTP monkeys, the high dyskinetic potential of several selective D2 agonists and the more favorable outcome on dyskinesia resulting from the continuous stimulation of D2 receptors (leading to D2 receptor down regulation) are important clues suggesting the primary role played by D2 receptor-mediated mechanisms in the dyskinesia priming process. Further clinical studies using drugs selective for the various dopamine receptor subtypes and of different efficacy half-lives are needed to validate our primate data.

Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia?

Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D1 receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half-life and selectivity in monkeys rendered parkinsonian following toxic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in "drug-naive" and "dyskinesia-primed" MPTP animals suggest that pathological sensitisation of D2 receptor-mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D1 receptors, and that repeated short-lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D1 agonists for further clinical testing.

Effect of nondopaminergic drugs on L-dopa-induced dyskinesias in MPTP-treated monkeys.

A group of four monkeys was rendered parkinsonian with the toxin MPTP. They were then treated chronically with L-DOPA/benserazide 50/12.5 mg/kg given orally daily for 2 months. This dose produced a striking antiparkinsonian effect, but all animals manifested dyskinesia. A series of agents acting primarily on neurotransmitters other than dopamine were then tested in combination with L-DOPA to see if the dyskinetic movements would be modified. Several drugs, including clonidine, physostigmine, methysergide, 5-MDOT, propranolol, and MK-801, markedly reduced the dyskinetic movements but at the cost of a return of parkinsonian symptomatology. However, yohimbine and meperidine reduced predominantly the dyskinetic movements. Baclofen was also useful in one monkey against a more dystonic form of dyskinesia. Atropine converted the dystonic movements into chorea.

Effect of clonidine and atropine on rest tremor in the MPTP monkey model of parkinsonism.

The purported alpha 2-adrenergic agonist clonidine was found to inhibit rest tremor at doses of 0.023-0.1 mg/kg in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of parkinsonism. The effect was dose dependent, but sedation and reduced mobility were observed. Atropine at doses of 0.1-1 mg/kg also reduced tremor in a dose-dependent fashion, but side-effects in the form of agitation, dilated pupils, and dry mouth were seen. When the two drugs were combined, however, we saw a significant potentiation of the antitremor effect. We could even abolish tremor with doses of atropine and clonidine that by themselves were without effect. The side-effects were almost eliminated by the combination.

Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.

OBJECTIVES: The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating over the range of 1.0 mg to 100 mg (free base equivalents). METHODS: This was a randomized, double-blind, single-dose, placebo-controlled, dose-escalation trial, with each dose group (1.0, 3.0, 10, 30, 50, 75 and 100 mg) having eight volunteers (six PNU-142633F and two placebo). Clinical laboratory tests, electrocardiogram, Holter monitoring, and assessment of adverse events were used to gauge the tolerability of PNU-142633. Serial blood samples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method. RESULTS: PNU-142633 was well tolerated after oral administration. There were no reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There were no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pressure, pulse rate or respiratory rate), at any study time or dose. There were no clinically significant ECG changes. Only sporadic abnormalities in clinical chemistry values and hematology were noted. After the 1.0 mg and 3.0 mg doses, plasma concentrations of PNU-142633 were either below or only slightly above the lower limit of quantitation (2 ng/ml). At higher doses (30-100 mg) the terminal half-life was relatively constant at approximately 11 hours. Neither Cmax nor AUC(0-infinity) increased proportionally with the administered dose. The mean percentage of the dose excreted in the urine as intact PNU-142633 increased from 14.3% after the 1 mg dose to 49.3% after the 100 mg dose. CONCLUSIONS: The clinical safety and pharmacokinetic data support the study of this agent as a potential treatment for migraine attacks.

Changes of AMPA receptors in MPTP monkeys with levodopa-induced dyskinesias.

Overactivity of glutamate neurotransmission is suspected to be implicated in Parkinson's disease and levodopa-induced dyskinesia. The fast glutamatergic transmission in the striatum from the cortex is mediated mainly by non-n-methyl-d-aspartate (non-NMDA) receptors. Animal models of Parkinson's disease reveal conflicting data concerning striatal glutamate AMPA receptors. The present study thus sought to shed light on the relationship of striatal AMPA receptors to the development of levodopa-induced dyskinesia. [(3)H]Ro 48-8587, a highly potent and selective-specific antagonist ligand for AMPA receptors, was used to investigate, by autoradiography, striatal AMPA receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated for 1 month with levodopa alone, levodopa+CI-1041 (NMDA receptor antagonist) or levodopa+cabergoline (D2 receptor agonist). Levodopa-treated MPTP monkeys developed dyskinesias while those that received levodopa+CI-1041 or levodopa+cabergoline did not. In the anterior caudate nucleus and putamen, specific binding of [(3)H]Ro 48-8587 was reduced in all MPTP-treated monkeys compared to control monkeys, but no significant effect of MPTP was measured in the posterior striatum. In dyskinetic monkeys, specific binding of [(3)H]Ro 48-8587 was elevated in subregions of the posterior caudate nucleus and putamen as compared to saline-treated MPTP monkeys. Levodopa+CI-1041 treatment left unchanged specific binding of [(3)H]Ro 48-8587 whereas levodopa+cabergoline treatment reduced it in subregions of the posterior caudate nucleus and putamen compared to control and levodopa-treated MPTP monkeys. Specific binding of [(3)H]Ro 48-8587 was low in the globus pallidus and remained unchanged following both lesion and treatments. In conclusion, the elevated values of AMPA receptors in dyskinetic monkeys (and their prevention through treatments) were only observed in subregions of the striatum.

Central nervous system drug development: an integrative biomarker approach toward individualized medicine.

Drug development for CNS disorders faces the same formidable hurdles as other therapeutic areas: escalating development costs; novel drug targets with unproven therapeutic potential; and health care systems and regulatory agencies demanding more compelling demonstrations of the value of new drug products. Extensive clinical testing remains the core of registration of new compounds; however, traditional clinical trial methods are falling short in overcoming these development hurdles. The most common CNS disorders targeted for drug treatment are chronic, slowly vitiating processes manifested by highly subjective and context dependent signs and symptoms. With the exception of a few rare familial degenerative disorders, they have ill-defined or undefined pathophysiology. Samples selected for treatment trials using clinical criteria are inevitably heterogeneous, and dependence on traditional endpoints results in early proof-of-concept trials being long and large, with very poor signal to noise. It is no wonder that pharmaceutical and biotechnology companies are looking to biomarkers as an integral part of decision-making process supported by new technologies such as genetics, genomics, proteomics, and imaging as a mean of rationalizing CNS drug development. The present review represent an effort to illustrate the integration of such technologies in drug development supporting the path of individualized medicine.

Effect of D1 and D2 agonists and antagonists on dyskinesia produced by L-dopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys.

A group of five cynomolgus monkeys was rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then treated daily with levodopa until all animals developed evident dyskinesia in the limbs after each dose. At this point, levodopa was replaced by selective D2 and D1 dopamine receptor agonists. All D2 agonists including quinpirole, (+)-4-propyl-9-hydroxynaphthoxazine, bromocriptine, terguride and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperone reproduced the same dyskinesia, the intensity and duration of which was dose-dependent and paralleled the therapeutic effect. One D1 agonist, SFK-38393, was without effect (antiparkinsonian and dyskinetic) whereas another, CY-208243, induced antiparkinsonian at a low dose but also a dyskinetic effect at a higher dose. The effect of the selective agonists were antagonized completely by their corresponding antagonist but partially by the noncorresponding one. The effect of either D1 and D2 agonist was totally suppressed by the dopamine depleting agent alpha-methyl-p-tyrosine, but the effect was restored by a small subthreshold dose of the other (complementary) agonist. Our results thus indicate that dyskinesia cannot be ascribed solely to the D2 or the D1 receptor and that some cooperation between the two receptors appears necessary for their manifestation.

Effect of chronic treatment with (+)-PHNO, a D2 agonist in MPTP-treated monkeys.

A group of four drug naive Macaca fascicularis were rendered parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine and then treated chronically with (+)-PHNO, a potent D2 agonist. After several days, dyskinesia appeared in all animals. At this point, the daily dose of (+)-PHNO was replaced by a dose of the D1 agonist CY 208-243. The substitution by CY 208-243 reproduced the same dyskinesia observed with (+)-PHNO. The administration of the DA synthesis inhibitor AMPT (alpha-methyl-p-tyrosine methyl ester) blocked the dyskinetic and antiparkinsonian effect of (+)-PHNO, and those effects were reestablished by the addition of a subthreshold dose of CY 208-243. Our results show that a selective D2 agonist is capable of inducing dyskinesia and suggest some kind of cooperation between D1 and D2 receptors in the antiparkinsonian and dyskinetic effect produced by (+)-PHNO.

Effect of LY 171555 and CY 208-243 on tremor suppression in the MPTP monkey model of parkinsonism.

The antitremor effect of the D2 agonist LY 171555 and of the D1 agonist CY 208-243 alone and in combination was tested in a monkey previously rendered parkinsonian by MPTP and displaying exceptionally a rest tremor in the limbs. The D2 agonist suppressed rest tremor in a dose-dependent fashion. The D1 agonist by itself had no effect but it potentiated the effect of a small dose of LY 171555.

Ethosuximide and tremor in Parkinson's disease: a pilot study.

Following the demonstration of an anti-tremor effect of ethosuximide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, we have tested the effect of this drug in 10 patients with typical parkinsonian tremor. Six patients suffered from Parkinson's disease with prominent, relatively drug-resistant rest tremor. The other four patients had a drug-induced parkinsonian tremor due to neuroleptic agents taken for a psychiatric condition. Five of the six parkinsonian patients and three of the four psychiatric patients reported within a few days a marked and intolerable exacerbation of their tremor. One patient in each group was improved, and this improvement was verified in repeated examinations. Thus, for unknown reasons, the effect of ethosuximide was not as predicted by the monkey model. Among possible explanations is the fact that we had chosen patients with drug-resistant tremor.