The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. METHODS: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95-1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83-1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08-1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319-1·458) compared with 1·222 (1·110-1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. INTERPRETATION: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Bidirectionality of antiseizure and antipsychotic treatment: A population-based study.

PURPOSE: To study the prevalence and directionality of comorbid epilepsy and psychosis in Norway. METHODS: The Norwegian Prescription Database (NorPD) provided individual-based information on all antiseizure medications (ASMs) and antipsychotic drugs (APDs) dispensed during 2004-2017. Subjects were ≥18 years of age at the end of the study period. Diagnosis-specific reimbursement codes from the 10th revision of the International Classification of Diseases/2nd edition of the International Classification of Primary Care (ICD-10/ICPC-2) combined with ATC codes were used as indicators of diagnosis. Subjects had collected ASMs for epilepsy or APDs for psychosis at least four times, at least once issued with an ICD-10 code from the specialist healthcare service. Directionality was analyzed in subjects receiving both treatments. To reduce prevalent comorbidity bias, we employed a four-year comorbidity-free period (2004-2007). The use of specific ASMs and APDs was analyzed. RESULTS: A total of 31,289 subjects had collected an ASM for epilepsy at least four times, 28,889 an APD for psychosis. Both the prevalence of treatment for epilepsy and of treatment for psychosis was 0.8%. Further, 891 subjects had been treated for both conditions; 2.8% with epilepsy had been treated for psychosis, and 3.1% with psychosis had been treated for epilepsy. Among 558 subjects included in the analyses of directionality, 56% had collected the first APD before an ASM, whereas 41% had collected an ASM first. During the last year prior to comorbidity onset, levetiracetam, topiramate, or zonisamide had been used for epilepsy by approximately 40%, whereas olanzapine and quetiapine were most used in patients with psychosis, and clozapine in 13%. CONCLUSION: The proportion of patients with prior antipsychotic treatment at onset of epilepsy is higher than previously acknowledged, as demonstrated in this nation-wide study. Apart from a shared neurobiological susceptibility, the bidirectionality of epilepsy and psychosis may be influenced by various environmental factors, including the interaction of pharmacodynamic effects. APDs may facilitate seizures; ASMs may induce psychiatric symptoms. In patients with combined treatment, these potential drug effects should receive ample attention, along with the psychosocial consequences of the disorders. A prudent multi-professional approach is required.

Long-term effect of antiepileptic drug switch on serum lipids and C-reactive protein.

BACKGROUND: Prior studies have shown that switching patients from inducing antiepileptic drugs (AEDs) to lamotrigine, levetiracetam, or topiramate reduces serum lipids and C-reactive protein (CRP). These studies were all of short duration, and some drugs, such as zonisamide, have not been investigated. METHODS: We recruited 41 patients taking phenytoin or carbamazepine who were being switched to zonisamide, lamotrigine, or levetiracetam. We measured serum lipids and CRP before the switch, >6weeks after, and >6months after. An untreated control group (n=14) underwent similar measurement. We combined these data with those of our previous investigation (n=34 patients and 16 controls) of a very similar design. RESULTS: There were no differences in outcome measures between the two inducing AEDs nor among the three noninducing AEDs. Total cholesterol (TC), atherogenic lipids, and CRP were higher under inducer treatment than in controls. All measures were elevated under inducer treatment relative to noninducer treatment, including TC (24mg/dL higher, 95% CI: 17.5-29.9, p<0.001) and CRP (72% higher, 95% CI: 41%-111%, p<0.001). The difference between drug treatments was clinically meaningful for atherogenic lipids (16%, 95% CI: 11%-20%, p<0.001) but small for high-density lipoprotein cholesterol (5%, 95% CI: 1%-9%, p<0.05). All measures were stable between 6weeks and 6months after drug switch. CONCLUSIONS: We demonstrate that switching from inducing to noninducing AEDs produces an enduring reduction in serum lipids and CRP. These results provide further evidence that inducing AEDs may be associated with elevated vascular disease risk. These are the first vascular risk marker data in patients taking zonisamide, which shows a profile similar to that of other noninducing AEDs.

Retention rate of zonisamide in intractable epilepsy.

OBJECTIVES: To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-to-treat epilepsy in adult Scandinavian patients. MATERIAL AND METHODS: 151 outpatients (mean age: 42.5 years) from 18 centres in Denmark, Sweden and Norway were recruited to the study. 81.5% had focal epilepsy, and the mean number of previously tried AEDs was 4.5. The patients were given ZNS as add-on treatment, and the ZNS dosing and the visit frequency were governed by the treating physician. The primary efficacy endpoint was the retention rate after 12-month treatment. Assessments included also responder rate, type and frequency of adverse events, healthcare resource utilization (HCRU) and quality of life (QOLIE-31). RESULTS: 90 patients (59.6%) completed the study. Mean daily ZNS dose was 300.8 mg. After 12 months, 81 patients were still on ZNS, that is a retention rate of 53.6%. The mean reduction of seizure frequency at 12 months was 27%. Best effect was seen in those with focal and those with secondary generalized seizures. In the QOLIE-31, there was a mean increase from baseline of 4.8 points. The tolerability was generally good. The majority of side effects were CNS-related, dizziness, fatigue, seizure aggravation, and headache being most prevalent. 21.2% had adverse events leading to withdrawal of ZNS. CONCLUSIONS: A retention rate of 53.6% after 1 year of treatment with ZNS is roughly in accordance with the retention rates found for lamotrigine, oxcarbazepine, levetiracetam and topiramate in drug-resistant patients.

Lacosamide-induced atrial tachycardia in a child with hypoplastic left-heart syndrome: the importance of assessing additional proarrhythmic risks.

Antiepileptic medications have been reported to cause disturbances in cardiac conduction. Lacosamide decreases seizure burden by modulating sodium channels. Although it has been demonstrated to have few side effects, there have been reports of clinically significant cardiac conduction disturbances. We report the case of a child with hypoplastic left-heart syndrome and well-controlled multifocal atrial tachycardia who developed haemodynamically significant atrial tachycardia after receiving two doses of lacosamide.

Safety and tolerability of zonisamide in elderly patients with epilepsy.

OBJECTIVES: To assess the safety/tolerability of zonisamide in elderly patients. MATERIALS & METHODS: A pooled analysis of clinical study data from elderly (≥65 years) patients receiving add-on/monotherapy zonisamide for partial seizures was compared with pooled adult (18-65 years) study data. Assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters and weight change. RESULTS: Data were analyzed from 95 elderly and 1389 adult patients. Incidence of total TEAEs was similar (elderly, 78/95 [82%] vs adult, 1165/1389 [84%]); but lower in elderly versus adult patients for treatment-related TEAEs (53/95 [56%] vs 1010/1389 [73%]), severe TEAEs (11/95 [12%] vs 289/1389 [21%]), serious TEAEs (12/95 [13%] vs 230/1389 [17%]) and TEAEs leading to withdrawal (17/95 [18%] vs 312/1389 [23%]). Most TEAEs were of mild-to-moderate intensity. TEAEs reported more frequently by elderly versus adult patients included fatigue (11/95 [12%] vs 135/1389 [10%]), nasopharyngitis (8/95 [8%] vs 100/1389 [7%]), constipation (7/95 [7%] vs 67/1389 [5%]) and pruritus (6/95 [6%] vs 29/1389 [2%]). The only serious TEAEs reported by ≥2% of elderly patients were 'convulsions' (4/95 [4%] vs 49/1389 [4%]). Three elderly patients died; one death was considered treatment-related. TEAEs leading to discontinuation of ≥2% of elderly patients were dizziness (4/95 [4%]), headache (2/95 [2%]), somnolence (2/95 [2%]) and confusional state (2/95 [2%]). For elderly patients, there were minimal changes in clinical laboratory parameters, no reports of respiratory alkalosis or metabolic acidosis and no significant weight changes. CONCLUSIONS: Zonisamide demonstrated a favourable safety/tolerability profile in elderly patients. No new or unexpected safety findings were identified.

[Bilateral urolithiasis with zonisamide developed for a short period of time in a 10-year-old girl with intractable epilepsy].

Zonisamide is an antiepileptic drug mainly used in patients with refractory epilepsy. One of the urological adverse effects caused by zonisamide is urinary lithiasis. We reported bilateral urinary lithiasis with zonisamide developed for a short period of time. A 10 year-old girl had been treated with zonisamide for intractable epilepsy for nine years. She progressively developed microscopic hematuria as well as crystalluria while being hospitalized for ventriculoperitoneal shunt infection. A computed tomography (CT) showed bilaterally hydronephrotic kidneys obstructed by multiple ureteral calculi. What was impressive was the fact that any single urinary calculus was not identified in a CT image taken just three weeks prior to this event. Then the diagnosis was made of zonisamide-induced bilateral urinary calculi and zonisamide treatment was discontinued. However, since the deterioration of renal function and left-sided hydronephrosis progressed, we performed the construction of right-sided percutaneous nephrostomy (PNS) and the transurethral placement of a left ureteral stent. Subsequently her condition was stabilized and all of these stones were discharged. The analysis of these stones showed mainly calcium phosphatic calculus. We eventually removed both the right PNS and the left ureteral stent. Since then, there has not been any recurrence thus far. We need to recognize the risk of progressively developing renal calculi during zonisamide treatment for a relatively short period of time in the face of dehydration.

Zonisamide versus diazepam in the treatment of alcohol withdrawal syndrome.

INTRODUCTION: Anticonvulsant drugs have been used in the treatment of alcohol detoxification. The purpose of the present study was to evaluate the efficacy and safety of zonisamide in a sample of patients presenting alcohol withdrawal syndrome. METHOD: In this 3-week, randomized, flexible-dose trial, 40 inpatients with alcohol dependence disorder received zonisamide or diazepam for detoxification. Zonisamide was started at a dose of 400-600 mg/day (week 1), tapering to a minimum dose of 100-300 mg/day (week 3). Diazepam was administered using a similar regimen (from 130-50 mg/day tapering to 5-15 mg/day). Subjects were treated initially (weeks 1 and 2) in an inpatient unit and for the final week in an outpatient facility. During the inpatient period, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) was used to assess the efficacy of each substance. During the outpatient period the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and a craving scale were used. RESULTS: All subjects completed the study. During the inpatient period both drugs reduced alcohol withdrawal symptoms, but the decrease was more marked in the zonisamide group. At the end of the study (week 3) participants treated with zonisamide showed lower CIWA-Ar scores than subjects receiving diazepam. Also, individuals in the zonisamide group had less craving for alcohol, less anxiety, and less daytime sedation compared with participants treated with diazepam. CONCLUSION: Zonisamide can be a valuable alternative to benzodiazepines in the prevention of alcohol withdrawal syndrome.

Comparison of zonisamide with non-levodopa, anti-Parkinson's disease drugs in the incidence of Parkinson's disease-relevant symptoms.

INTRODUCTION: Patients with Parkinson's disease (PD) experience various symptoms, both from the disease progression itself and the medication. Few large-scale studies have investigated the associations between zonisamide and these symptoms. This study compared zonisamide and other anti-PD drugs by analyzing their associations with the incidence of PD-relevant symptoms. METHODS: This was a cohort study based on claims data from Diagnosis Procedure Combination hospitals between 2008 and 2014 in Japan. Patients were included in the cohort if they were diagnosed with PD, aged ≥40 years, and were prescribed anti-PD drugs from the same single class without switching to/combination use with other classes excepting levodopa. The outcomes were the incidence of PD-relevant symptoms from the following categories; mental/psychiatric, autonomic nervous system, motor-related, and gastric symptoms. The associations between the incidence of these symptoms and the prescriptions of 8 different classes of anti-PD drugs were explored by the survival analysis. RESULTS: In the final cohort, 9157 patients were included. The zonisamide use was significantly associated with a lower risk of dementia, insomnia, and gastric ulcers than 3 of 7 other classes without levodopa (p < .05). CONCLUSION: There may be a potential clinical impact of zonisamide on some of the PD-relevant symptoms.

An evaluation of zonisamide, including its long-term efficacy, for the treatment of focal epilepsy.

INTRODUCTION: About 70 million people worldwide are estimated to suffer from epilepsy. Despite a large variety of old and new antiepileptic drugs on the market, about 30% of people with epilepsy do not become seizure-free with medical treatment. This is a major individual and public health burden. Most of these difficult-to-treat patients are having focal seizures. Zonisamide is effective against focal seizures in adults and children and, thus, a therapeutic option for such patients. Its safety profile needs special attention. Areas covered: Herein, the authors discuss the pharmacology, clinical efficacy and the adverse effects of zonisamide. The article is derived from clinical trial data, long-term studies, meta-analyses, review articles, text books, webpages, and official license information. Expert opinion: Zonisamide has proven to be efficacious in focal epilepsy in children and adults, although it is not more effective than carbamazepine or other antiepileptic drugs. It is also effective in generalized epilepsy and in several other conditions of the CNS. Its safety profile may prevent it from becoming a first-line drug for focal epilepsy or any other indication.

Novel anticonvulsant drugs.

Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.

[Clinical experience of using zonisamide in structural focal epilepsy in children with cerebral palsy]. / Klinicheskii opyt primeneniia zonisamida pri strukturnoi fokal'noi épilepsii u detei s detskim tserebral'nym paralichom.

AIM: To evaluate the efficacy and safety of zonisamide as an add-on therapy in structural focal epilepsy in children with cerebral palsy (CP). MATERIAL AND METHODS: Sixty-four patients (36 boys and 28 girls) with spastic CP and structural focal epilepsy with refractory seizures were followed up. Patients received zonisamide in a dose of 6-8.8 mg/kg/day for ≥6 months. Treatment efficacy was assessed by the reduction of seizures depending on CP form, type of epileptic seizures, combination of zonisamide with other drugs and adverse-effects. RESULTS AND CONCLUSION: A reduction of seizures by ≥50% was identified in 60.9% of children, 10.9% showed a better recovery. The best efficacy (35.9%) was demonstrated in the treatment of generalized seizures with focal onset and in the combination with levetiracetam (35.9%). Adverse effects of mild to moderate severity were noted in 26.5% of children. The treatment was discontinued in 7.8%. Therefore, zonisamide is an effective treatment for refractory structural focal epilepsy in children with CP and comorbid pathology, which reduces the frequency of seizures without severe side-effects.

[New medications; zonisamide]. / Nieuwe geneesmiddelen; zonisamide.

Zonisamide is an adjuvant for the treatment of patients with partial epilepsy, with or without secondary generalisation. It affects, among other things, the voltage-sensitive sodium and calcium channels, thus disrupting synchronised neuronal firing; as a result, it diminishes the spread of seizure discharges.

Retention, dosing, tolerability and patient reported seizure outcome of Zonisamide as only add-on treatment under real-life conditions in adult patients with partial onset seizures: Results of the observational study ZOOM.

PURPOSE: Zonisamide is licensed for adjunctive therapy for partial-onset seizures with or without secondary generalisation in patients 6 years and older and as monotherapy for the treatment of partial seizures in adult patients with newly diagnosed epilepsy, and shows a favourable pharmacokinetic profile with low interaction potential with other drugs. The aim of the present study was to gather real-life data on retention and modalities of zonisamide use when administered as only add-on treatment to a current AED monotherapy in adult patients with partial-onset seizures. METHODS: This multicenter observational study was performed in 4 European countries and comprised three visits: baseline, and after 3 and 6 months. Data on patients' retention, reported efficacy, tolerability and safety, and quality of life was collected. Of 100 included patients, 93 could be evaluated. RESULTS: After 6 months, the retention rate of zonisamide add-on therapy was 82.8%. At this time, a reduction of seizure frequency of at least 50% was observed in 79.7% of patients, with 43.6% reporting seizure freedom over the last 3 months of the study period. Adverse events were reported by 19.4% of patients, with fatigue, agitation, dizziness, and headache being most frequent. Approximately 25% of patients were older than 60 years, many of whom suffered from late-onset epilepsy. Compared to younger patients, these patients showed considerable differences with regard to their antiepileptic drug regimen at baseline, and slightly higher responder and retention rates at 6 months. CONCLUSIONS: Despite limitations due to the non-interventional open-label design and the low sample size, the results show that zonisamide as only add-on therapy is well retained, indicating effectiveness in the majority of patients under real-life conditions.

A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients.

OBJECTIVE: The purpose of this study was to investigate the effectiveness of zonisamide in the treatment of bipolar depression. METHOD: Ten patients with DSM-IV bipolar disorder, depressed phase, who had either not tolerated or not responded to previous treatments were given zonisamide in this add-on open-label study. Zonisamide treatment was started at 100 mg/day and increased by 100 mg every 2 weeks to a maximum of 300 mg/day in divided doses (b.i.d. or t.i.d.). Subjects underwent weekly visits at which they were administered the 17-item Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale (CGI). Every 2 weeks, subjects also underwent laboratory tests, a urine examination, and a verbal memory test. Outcome measures were analyzed with repeated-measures analysis of variance. RESULTS: Eight subjects completed all 8 weeks of the study. Two subjects completed more than 4 weeks of the study, and their data were analyzed using the last observation carried forward. Bipolar depression subjects had a significant reduction in HAM-D scores (p < .001) and in CGI-Improvement (CGI-I) scores (p < .001). Five of 8 subjects who completed all 8 weeks of the study had more than a 50% decrease in HAM-D scores and were rated much improved on the CGI-I at the end of 8 weeks of treatment. There was no significant drug effect on YMRS scores, weight, or verbal memory. CONCLUSION: Zonisamide may be a useful drug in the treatment of bipolar depression. Further controlled clinical trials are needed.

Newer anticonvulsants in the treatment of bipolar disorder.

The anticonvulsants valproate and carbamazepine have efficacy in treating acute mania, but their efficacy in treating acute bipolar depression and preventing mood episodes remains uncertain. Despite this, and given their utility and widespread use, both are widely accepted as standard treatments for bipolar disorder. All the newer anticonvulsants that have become available during the last decade have been or are being assessed to determine their efficacy in the treatment of various phases of bipolar disorder. Among the newer anticonvulsants, some appear to have efficacy in treating core bipolar symptoms, while others have efficacy in treating psychiatric comorbidity such as substance abuse or an anxiety disorder. Lamotrigine is the most widely studied and is effective in treating and preventing bipolar depression, and it is the only anticonvulsant approved by the U.S. Food and Drug Administration as a maintenance treatment for bipolar disorder. Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy in treating acute mania, but their utility in bipolar depression and prevention of mood episodes has not been studied in double-blind trials. Pregabalin has utility in treating generalized anxiety disorder, but it has not been studied in bipolar disorder. Given the success of lamotrigine in treating bipolar disorder, further double-blind controlled trials of the newer anticonvulsants in treating bipolar disorder are warranted. This article summarizes current evidence from trials of anticonvulsants in bipolar disorder and makes recommendations for their clinical use.

Zonisamide has beneficial effects on Parkinson's disease patients.

Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinson's disease (PD). ZNS (300 mg/day) given to a patient with PD who incidentally had convulsive attacks, ameliorated the attacks and, surprisingly, his parkinsonian symptoms. We, therefore, carried out an open trial of ZNS on nine patients with PD. Patients were given 50-200 mg/day ZNS in addition to their anti-PD drugs. Seven clearly showed lessening of symptoms, especially wearing-off. We speculate that long lasting activation of dopamine synthesis by ZNS ameliorates parkinsonian symptoms, in particular wearing-off.