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There has been continuous progress in neurotherapeutics and neuropsychopharmacology in the past year. Notable are the reports of successful preliminary disease-modifying trials in Niemann-Pick disease and Friedreich's ataxia. Progress also has been made in treatment of migraine, stroke, epilepsy, multiple sclerosis, traumatic brain injury, and pain. Biomarkers are increasingly used to establish proof of pharmacology including measures of cerebrospinal fluid constituents and brain changes on magnetic resonance imaging. There is an increasing diversity of patient populations participating in clinical trials, including pediatric migraine and traumatic brain injury.

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Antiplatelet agents represent an important part of the therapeutic armamentarium in the prevention of stroke. Triflusal is an antiplatelet agent structurally related to salicylates but not derived from acetylsalicylic acid. Like aspirin, triflusal irreversibly acetylates cyclo-oxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. Triflusal is rapidly absorbed after oral administration, with an absorption half life of 0.44 hours. Evidence of the efficacy and safety of triflusal is derived from clinical trials performed in patients with unstable angina, acute myocardial infarction, stroke, aortocoronary by-pass, atrial fibrillation, valve replacement, and asthmatic patients intolerant to aspirin and/or non-steroidal antiinflamatory drugs (NSAID). The Triflusal versus Aspirin for the Prevention of Infarction: A Randomized Stroke Study (TAPIRSS) study was performed to explore the efficacy and safety of triflusal versus aspirin in the prevention of vascular complications in patients with a previous TIA or ischemic stroke in a Latin American population. In this pilot study differences between triflusal and aspirin in the prevention of vascular complications after TIA or ischemic stroke were not observed. Hemorrhagic risk was lower with triflusal than with aspirin. The TAPIRSS study contributed evidence on the efficacy and safety of triflusal as a valid alternative to aspirin in the prevention of vascular events in patients with ischemic stroke or TIA.

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Background: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke is related to clot lysis and arterial recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. However, human data on this combination are limited. Design: We report an update of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose escalation, safety, and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 h. After standard dose intravenous rtPA administration, a 100-μg/kg bolus of argatroban followed by infusion of 1 μg/kg per min for 48 h was adjusted to a target partial thromboplastin time of 1.75 times baseline. Results: Twenty patients with middle cerebral artery occlusions (including 13 men) have been enrolled, with a mean ± SD age of 61 ± 13 years. Baseline median National Institute of Health Stroke Scale score was 12.5 (range, 3–25). The mean ± SD time from symptom onset to argatroban bolus administration was 177 ± 56 min. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 2 patients and there was 1 death. Recanalization was complete in 7 patients and partial in another 7, and reocclusion occurred in 4 within 2 h of rtPA bolus administration. Conclusion: The combination of low-dose argatroban and intravenous rtPA may be safe, and produce faster and more complete recanalization, but a larger cohort of patients is required to confirm this pilot study.

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The MONOCOMB study was a double-blind, randomized, controlled trial initiated to examine the impact of selegiline monotherapy on time to the start of levodopa therapy and, subsequently, to compare the progression of PD in patients treated with individualized levodopa plus selegiline or placebo.

Previously untreated patients with idiopathic PD (N = 157) were randomized to receive selegiline 10 mg/day or placebo until levodopa was required; experimental medication was then withdrawn for 8 weeks. Patients were then randomized to levodopa (50 mg/day, titrated in 50 mg/day increments to 150 mg/day) plus either selegiline or placebo. Treatment was continued until patients required additional antiparkinsonian therapy or up to 7 years after initial randomization. The primary efficacy outcome for the monotherapy phase of the study was time to introduction of levodopa. Primary efficacy endpoints for the combined therapy phase were: time to development of fluctuations in disability; and time to the addition of supplementary antiparkinsonian treatment.

Selegiline significantly delayed the time when levodopa therapy became necessary during the monotherapy phase, although mean total UPDRS scores at time of initiation of levodopa were similar in both groups. Selegiline was also associated with improvements in PD' symptom status and disability as reflected in a broad range of well-established indices. After the 8 week wash out period the disability of the clinical condition of the patients in the selegiline group was still significantly better in the selegiline group than in the placebo group. During the combination phase of the study, the use of selegiline as an adjunct to levodopa enabled a given degree of therapeutic effect to be achieved with a demonstrably lower total consumption of levodopa. Patients treated with selegiline plus levodopa also exhibited a distinct (p = 0.005) slowing in the anticipated increase in the UPDRS scores over time, as for example in a mean UPDRS total score after 5 years 10 points lower than in patients on levodopa and placebo. The emergence of motor (wearing-off) fluctuations was delayed by selegiline, and the proportion of patients experiencing these events was lower than with placebo (20% versus 34%; p = 0.053).

Mild gastrointestinal events were significantly more common with selegiline monotherapy than with placebo (12 versus. 3; p = 0.028). The overall rates of AEs during the combination therapy phase were 69% in the selegiline group and 54% in the placebo group (p = 0.053). Significantly more patients in the selegiline group reported nausea. Of the five deaths that occurred during the combination therapy phase of the study (selegiline N = 4, placebo N = 1) none was expressly attributed to study medication.

The results of MONOCOMB, among the largest and longest-duration placebo-controlled studies to report experience with selegiline monotherapy in early-phase PD, confirm that selegiline is effective in retarding the progression of early PD, that it has levodopa-sparing qualities in more advanced disease, and that it is reasonably well-tolerated in long-term use.

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This chapter reviews the EASE PD - Adjunct trial which is a double-blind, placebo-controlled, 24-week study of 393 Parkinson disease (PD) subjects with levodopa-induced motor fluctuations randomized to ropinirole 24-h prolonged release or placebo. The objective of the trial was to assess the efficacy and tolerability of once daily ropinirole 24-h prolonged release as an adjunct to levodopa. The primary outcome variable was the reduction in daily “off” time as measured by subject diaries which was significantly reduced by 2.1 h with ropinirole 24-h prolonged release (mean dosage: 18.8 mg/day) compared to 0.3 h with placebo. There were also significant improvements in daily “on” time, “on” time without troublesome dyskinesia, Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living subscales, depression, quality of life and sleep with ropinirole 24-h prolonged release compared to placebo. The most common adverse events with ropinirole 24-h prolonged release were dyskinesia, nausea, dizziness, somnolence, hallucinations and orthostatic hypotension. Ropinirole 24-h prolonged release was well tolerated and led to improvements in both motor and non-motor symptoms of PD.

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Insulin and insulin resistance likely play a significant role in the pathophysiology and cognitive decline associated with Alzheimer's disease (AD). Insulin, insulin receptors, and insulin-sensitive glucose transporters are selectively localized the brain, including medial temporal areas that support memory. Raising brain insulin levels can facilitate memory and increase cerebrospinal fluid levels of β-amyloid (Aβ) and inflammatory markers. Insulin's effects on cognition may reflect normal regulation of glucose metabolism, long-term potentiation, and neurotransmitter levels. Consequently, insulin abnormalities may disrupt normal memory functioning and promote pathophysiological processes observed in patients with neurodegenerative disorders. Conversely, restoring normal insulin activity may exert a beneficial effect on pathophysiological processes. For example, peroxisome proliferator-activated receptor (PPAR)-gamma agonists (insulin sensitizing agents used to treat type 2 diabetes mellitus) modulate neuronal cell survival, inflammatory responses, mitochondrial functioning, and possibly Aβ processing and deposition. One PPAR-gamma agonist, rosiglitazone, facilitates memory and modulates plasma Aβ levels in patients with AD. Likewise, a healthy diet and regular exercise may improve insulin sensitivity and decrease the risk for both AD. Furthermore, intranasal insulin administration rapidly delivers insulin to the brain without altering plasma insulin or glucose levels. Studies to date suggest that this procedure can facilitate memory and modulate plasma Aβ levels in memory-impaired adults. Interestingly, the adverse effects of insulin abnormalities and the beneficial effects of improving insulin sensitivity may differ by apolipoprotein E (APOE) genotype, an established risk factor for AD. Patients who do carry lower doses of the APOE e4 allele have an enhanced risk for insulin abnormalities and are also more responsive to the memory enhancing effects of both rosiglitazone and intranasal insulin administration, relative to other patients. Therefore, future therapeutic trials should consider the moderating effects of APOE genotype.

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Background: Tramiprosate (3-amino-1-propanesulfonic acid, 3APS, ALZHEMED™) is an investigational product candidate that is believed to reduce amyloid deposition in the brain by binding to soluble Aβ, thereby slowing or halting the progression of Alzheimer Disease (AD). Design and Methods: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of tramiprosate in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or tramiprosate 50, 100, or 150 mg BID for 3 months. At the end of the double-blind study, 42 of these patients entered an open-label extension study in which they received tramiprosate 150 mg BID for an additional 17 months. Assessments included plasma and CSF tramiprosate concentrations, CSF Aβ42 concentrations, and psychometric tests (Alzheimer's Disease Assessment Scale – cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating Scale – Sum of Boxes). Results: Tramiprosate had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild-to-moderate in severity. Overall, six tramiprosate-treated patients discontinued because of side effects (all causalities) and there were no drug-related serious adverse events. Tramiprosate crossed the blood–brain barrier and dose-dependently reduced CSF Aβ42 levels after 3 months of treatment. There were no psychometric score differences between treatment groups after 3 months of double-blind treatment. However, psychometric score changes over the 17-month open-label extension study are consistent with a slowing of cognitive and clinical decline, particularly in mild subjects. Interpretation: Long-term administration of tramiprosate is safe and tolerated in patients with mild-to-moderate AD. The short-term reduction of CSF Aβ42 levels and the long-term open-label cognitive and clinical assessments are consistent with disease-modification.

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Background: Cluster headache is a form of primary headache characterized by short-lasting, excruciating unilateral head pains, associated with cranial autonomic features. The current gold-standard treatments of acute cluster headache are inhaled oxygen and sumatriptan by injection. The aim of the study was to evaluate zolmitriptan nasal spray (ZNS) in the acute treatment of cluster headache. Design/Methods: Ninety-two patients, aged 42 ± 10 years, 80 males and 12 females, with International Headache Society defined cluster headache were randomized into a placebo-controlled double-blind crossover study. One attack was treated with each of placebo, zolmitriptan nasal spray 5 and 10 mg (ZNS5, ZNS10). The primary endpoint was headache relief at 30 min: reduction from moderate, severe or very severe pain to nil or mild. The study was multi-center and multi-national, and was approved by the appropriate Ethics Committees. Results: Sixty-nine patients were available for an intention-to-treat analysis. The 30 min headache relief rates were: placebo 21%, ZNS5 40% and ZNS10 62%. Modeling the response as a binary outcome with regression methods, the Wald test was significant for the overall regression (χ2 = 29.4, p < 0.001), with both ZNS5 and ZNS10 giving significant effects against placebo. Headache relief rates for patients with episodic cluster headache were 30% for placebo, 47% for ZNS5 and 80% for ZNS10 while corresponding rates for patients with chronic cluster headache were 14%, 28% and 36%, respectively. Zolmitriptan intranasal was well tolerated. Interpretation: Zolmitriptan 5 and 10 mg intranasal is effective within 30 min and well tolerated in the treatment of acute cluster headache.

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Background: Though indications of a dose–response for glatiramer acetate (GA) were apparent during early drug development and clinical testing, no formal dose-comparisons of GA had been conducted before the present study. Design/Methods: This multicenter, randomized, double-blind study compared the safety and efficacy of two GA doses: 20 mg/day, the currently approved dose, versus 40 mg/day. Relapsing–remitting multiple sclerosis (RRMS) patients with active disease (1–15 gadolinium-enhancing (GdE) lesions on screening magnetic resonance imaging (MRI) and ≥1 relapse in the previous year) were eligible. The primary outcome was change from baseline in total number of GdE lesions at 7, 8, and 9 months. Other outcomes included effects on relapse, changes in expanded disability status scale (EDSS) scores, and responder analyses. Results: Benefits of the 40 mg GA dose versus the 20 mg dose on GdE lesions were evident by month 3. Additionally, significant advantages of the 40 mg dose were observed for time to first relapse and proportion of relapse-free patients. There was a trend for better outcomes with 40 mg/day GA for the primary efficacy measure, but the difference between doses was not statistically significant. Both GA doses were safe and similarly well tolerated. Interpretation: A 40 mg/day GA dosage may be more effective than the 20 mg/day recommended dosage for reducing disease activity, and appears to have an earlier onset of action. A large, phase III study is underway to confirm these findings.

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Background: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to trientine for the initial therapy of neurologic Wilson's disease.

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Background: Traumatic brain injury (TBI) is one of the major causes of death and disability among young people. Methylphenidate is a neural stimulant with possible brain protection properties and has been mainly used in clinic for childhood attention deficit/hyperactivity disorder. TBI patients with late psychosocial problems could benefit from methylphenidate because of the effect on arousal and consciousness level in the sub-acute phase. We studied this effect during the acute phase of moderate and severe TBI. Design and Methods: Forty patients with severe TBI (GCS = 5–8) and 40 moderate TBI patients (GCS = 9–12) were randomly divided into treatment and placebo groups on the day of admission. Treatment group received methylphenidate 0.3 mg/kg two times a day orally, beginning on the second day of admission and continuing until being discharged. Admission information and daily Glasgow Coma Scale (GCS) were recorded. Medical, surgical, and discharge plans for patients were decided by attending physicians, who were kept blinded during the course of treatment. Results: In the severe TBI patients, both hospital and ICU length of stay, on average, were shorter in the treatment group compared with the control group. In the moderate TBI patients, ICU stay was shorter in the treatment group, there was no significant reduction of the period of hospitalization. Interpretation: There were no significant differences between the treatment and control groups in terms of age, sex, post-resuscitation GCS, or brain scan findings, in either severely or moderately impaired TBI patients. Methylphenidate was associated with reductions in ICU and hospital length of stay by 23% in severe TBI patients (p = 0.06 for ICU and p = 0.029 for hospital stay time), in the moderately TBI patients who received methylphenidate, there was 26% fall (p = 0.05) in ICU length of stay.

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Background: Anti-epileptic drugs (AEDs) are associated with cognitive side effects. Doubt exists regarding the degree of cognitive effects primarily related to problems with design and methodology in many studies. The aim of the reported study was to assess the effect of AED withdrawal in patients on monotherapy using computerised measures of attention, reaction time and speed of information processing. Methods: One hundred and fifty patients seizure free >2 years on drug monotherapy went through a randomised, double blind, placebo controlled study. All patients were included for 12 months or until seizure relapse. Cognitive function was assessed with the California Computerized Assessment Package at baseline and 7 months after withdrawal. Results: The major finding was that discontinuation of major AEDs significantly improved performance on tests that require complex cognitive processing under time pressure. The difference in speed of cognitive processing between the withdrawal and non-withdrawal groups was between 24 and 43 ms. No significant difference emerged between the groups on simple tasks of attention and reaction time. Most of the patients in the study were treated with carbamazepine and valproate. The outcome of carbamazepine withdrawal was similar to the outcome for the total study population while discontinuation of valproate only revealed a non-significant tendency in the same direction. Interpretation: The results suggest that seizure-free epilepsy patients on monotherapy can obtain improvement in speeded cognitive processing if they withdraw anti-epileptic treatment.

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Background: Antidepressant effects have been demonstrated with both high-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) (HFL-TMS) and low-frequency stimulation to the right prefrontal cortex (LFR-TMS). However, doubts remain about the extent of these reported treatment effects. Design and Methods: The study was a 6 week double-blind randomized sham-controlled trial of sequential bilateral rTMS (SBrTMS) in depression. The method consisted of 3 trains of LFR-TMS of 140 s duration at 1 Hz being applied daily followed immediately by 15 trains of 5 s duration of HFL-TMS at 10 Hz. Sham stimulation was applied using identical parameters, but with the coil angled at 45 degrees from the scalp resting on the side of one wing of the coil. Results: There was a significant difference in response between the two groups at the 2-week time-point (F(1,25) = 25.5, p < 0.001) and for the full duration of the study (F(5,44) = 3.9, p = 0.005). A significant proportion of the active study group met response (11/25) and remission criteria (9/25) by study end compared to the sham group (2 and 0/22). Interpretation: Bilateral rTMS treatment, involving the sequential application of both HFL-TMS and LFR-TMS, has substantial treatment efficacy in patients with treatment-resistant depression. The treatment response is clinically significant following 4–6 weeks of active treatment. Therefore this novel style of bilateral rTMS has the potential to become a substantive clinical intervention, although the study requires replication.

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Up to 60% of OCD patients do not respond to a regular serotonin reuptake inhibitor (SRI) treatment. The purpose of the present study was to determine whether polymorphisms of the serotonin transporter (5-HTT), 5-HT1Dβ, and 5-HT2A receptor genes affect the efficacy of SRI treatment in OCD. Ninety-one outpatients with primary OCD according to DSM-IV criteria consented to the study were randomly assigned a 12-week, double-blind trial to receive dosages titrated upward to 300 mg/day of venlafaxine, or 60 mg/day of paroxetine. Primary efficacy was assessed by the change from baseline on the Yale-Brown obsessive–compulsive scale (Y-BOCS), and response was defined as a ≥25% reduction on the Y-BOCS. All of the paroxetine treated patients, with the G/G genotype of the 5-HT2A polymorphism were responders (χ2 = 8.66, df = 2, p = 0.013). In the venlafaxine treated patients, the majority of responders carried the S/L genotype of the 5-HTTLPR polymorphism (χ2 = 9.71, df = 2, p = 0.008). The small group of patients who both carried the S/L genotype of the 5-HTTLPR polymorphism and the G/G genotype of the 5-HT2A polymorphism responded all to treatment.

The results of this study suggest that the response in paroxetine and in venlafaxine treated OCD patients is associated with the G/G genotype of the 5-HT2A polymorphism and with the S/L genotype of the 5-HTTLPR polymorphism, respectively.

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Objective: The goal of the study was to assess the efficacy of sertraline in the treatment of the night eating syndrome (NES). Method: Thirty-four outpatients diagnosed with NES were randomly assigned to receive either sertraline (n = 17) or placebo (n = 17) in an 8-week, double-blind, flexible-dose (50–200 mg/day) study. We used the mixed effects linear regression model to analyze change in the primary outcome measure, the Clinical Global Impression of Improvement Scale (CGI-I). Secondary outcomes included changes in the Night Eating Symptom Scale (NESS), the number of nocturnal awakenings and ingestions, total daily calorie intake after the evening meal, Clinical Global Impression of Severity Scale (CGI-S), Quality of Life Enjoyment and Satisfaction Scale (Q-LES), and weight. Results: Sertraline was associated with statistically significantly greater improvements than placebo in the CGI-I scale. As determined by a CGI-I score of ≤2 (much or very much improved), 12 subjects in the sertraline group (71%) were classified as responders versus only 3 in the placebo group (18%). There were also significant improvements in the NESS, CGI-S scales, Q-LES, frequency of nocturnal ingestions and awakenings, and calorie intake after supper. Overweight and obese subjects in the sertraline group (n = 14) lost a significant amount of weight by week 8 (mean = −2.9, SD = 3.8 kg) compared to those in the placebo arm (n = 13) (mean = −0.3, SD = 2.7 kg). Conclusions: In this 8-week trial, sertraline was effective in the treatment of NES and was well tolerated.

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Background: Although historically neglected in clinical research, negative symptoms of schizophrenia are now considered distinct targets of pharmacotherapy. While second-generation antipsychotic treatments were heralded as having a greater therapeutic impact on negative symptoms than their conventional antipsychotic counterparts, the size of this effect is modest. Adjunctive medications such as antidepressants offer limited efficacy, while stimulants have a poor risk–benefit profile. More recently, promising results have been demonstrated with pro-glutamatergic agents such as glycine or D-cycloserine, although a larger trial found no advantage with either agent compared with placebo. Modafinil, a novel wakefulness-promoting agent, is an intriguing candidate for adjunctive pharmacotherapy to treat negative symptoms in schizophrenia. We explored this therapeutic potential through a placebo-controlled trial of patients with prominent negative symptoms. Methods: We randomly assigned patients with schizophrenia or schizoaffective disorder to treatment with either modafinil or placebo for 8 weeks. Double-blind assessments of clinical symptoms and neurocognition were administered at baseline and every 2 weeks thereafter. Results: Twenty subjects were enrolled (N = 10 modafinil, N = 10 placebo). There were no significant differences between modafinil and placebo for changes in negative symptom ratings, the primary study endpoint. However, modafinil treatment was associated with a greater rate and degree of global improvement at study endpoint compared with placebo. No significant worsening of psychopathology was observed and modafinil was well-tolerated. Interpretation: Although no effect on negative symptoms was found, adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms. These findings support additional research into a potential role for modafinil in the treatment of negative symptoms in schizophrenia.

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Background: There is a great need to develop new antipsychotic agents. In addition to dopaminergic neurotransmission, glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia. The most compelling link between glutamatergic N-methyl-d-aspartate (NMDA) neurotransmission and schizophrenia concerns the mechanism of action of the psychotomimetic drug phencyclidine and the dissociative anesthetic, ketamine; both are NMDA antagonists. The psychosis induced by the NMDA antagonists causes not only positive symptoms similar to the action of dopaminergic enhancers but also negative symptoms and cognitive deficits typical of schizophrenia in normal volunteers and worsening of the psychotic symptoms in patients with schizophrenia. Accordingly, enhancing NMDA neurotransmission should benefit the symptoms of schizophrenia. Methods: Most clinical trials were done by the addition of the NMDA-enhancing agents, glycine, d-serine, d-alanine, d-cycloserine and sarcosine to the stable regimens of antipsychotics in double-blind, placebo-controlled designs. Results: When taken together, the trials of NMDA-enhancing agents in patients with chronic schizophrenia receiving stable dose of antipsychotics, the NMDA-enhancing agents were effective in the domains of negative symptoms, cognition, depression, positive symptoms and general psychopathology. The agents also significantly improved extrapyramidal symptoms. No significant side-effects or safety concerns emerged. Interpretation: In addition to testing more lead compounds, dose-finding and long-term trials are required to determine the optimal dose and functional improvement capacity of NMDA receptor agonist. The agents may also be applied to prevention and the treatment for prodromal phases of the illness.