Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: A randomized, double-blind, placebo-controlled study

Schizophrenia Research 150 (2013) 289–296

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Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: A randomized, double-blind, placebo-controlled study James B. Lohr a,b,c,⁎, Lianqi Liu a,b,c, Michael P. Caligiuri a, Taylor P. Kash b, Todd A. May a,b, Jody DelaPena Murphy a,b,c, Sonia Ancoli-Israel a,b,c a b c

Department of Psychiatry, University of California, San Diego (UCSD), La Jolla, CA, USA Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA

a r t i c l e

i n f o

Article history: Received 26 March 2013 Received in revised form 16 July 2013 Accepted 19 July 2013 Available online 9 August 2013 Keywords: Modafinil Schizophrenia Parkinsonism Excessive daytime sleepiness Negative symptoms Cognition

a b s t r a c t Objective: To examine the efficacy and safety of modafinil on parkinsonism and excessive daytime sleepiness (EDS), as well as on negative symptoms and cognitive abilities in patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) in a randomized double-blind placebo-controlled 8-week study. Methods: Twenty-four male patients, who were aged 20–63 years and on stable dose of second generation antipsychotic medications and with a negative symptom score of ≥20 on the Positive and Negative Syndrome Scale (PANSS), were randomized into either the modafinil (n = 12) or placebo (n = 12) group. The modafinil group received flexible does of modafinil 50–200 mg/day. Primary measurements were the Simpson-Angus Scale (SAS) for extrapyramidal side effects (EPS), the Epworth Sleepiness Scale (ESS), the PANSS and a neuropsychological (NP) test battery. Data were collected on Days 0, 14, 28, 42 and 56 for rating scales, and on Days 0, 28 and 56 for NP tests. Results: Mixed model analyses showed a significant group-x-time interaction for total SAS scores (P b 0.006), with scores decreasing in the modafinil group but remaining the same in the placebo group. There were no significant group-x-time interactions for scores of ESS (total), PANSS (total, positive and negative), and NP tests (composite and domains) (all P's N 0.5). No significant adverse events were observed. Conclusion: The data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. Further studies in larger samples and with longer study time are needed to test/confirm the beneficial effects of modafinil on motor function. Published by Elsevier B.V.

1. Introduction In the past two decades it has become clear that although current drugs for schizophrenia can often be quite effective, there remains a need for better approaches to treatment of the condition, particularly relating to the need for reduced side effects, such as parkinsonism, and also to reductions in specific symptoms such as negative and cognitive symptoms (Caligiuri et al., 1993; Susatia and Fernandez, 2009; Correll, 2011). Extrapyramidal signs (EPS), including parkinsonism, are the major part of side effects of antipsychotic medications (Tandon, 2011). The second generation antipsychotics (SGAs) usually have the advantage of causing less EPS, but other problems, such as metabolic side effects, ⁎ Corresponding author at: VA Healthcare System (MC 116A), 3350 La Jolla Village Drive, La Jolla, CA 92161, USA. Tel.: +1 858 642 3762; fax: +1 858 642 1447. E-mail address: [email protected] (J.B. Lohr). 0920-9964/$ – see front matter. Published by Elsevier B.V. http://dx.doi.org/10.1016/j.schres.2013.07.039

have motivated increasing use of the first generation agents in recent years (Rummel-Kluge et al., 2012; Meltzer, 2013). EPS are routinely treated with anticholinergics, but many patients may not have full response to these drugs, or cannot tolerate the adverse effects of anticholinergic medications (Desmarais et al., 2012). Thus, alternative remedies for EPS would be a welcome addition to psychopharmacological approaches for psychosis treatment. Modafinil, as an agent with demonstrable activating effects, has been suggested to potentially benefit negative and cognitive symptoms of schizophrenia (Scoriels et al., 2013), although its effects on motor signs are largely unknown. In terms of cognitive problems or negative symptoms, some studies have reported positive results. A four-week open label study by Rosenthal and Bryant (2004) found global improvement in 11 patients with schizophrenia. Hunter et al. (2006) found improvement in cognitive functioning in patients with poorer baseline functioning. A single dose of 200 mg modafinil showed a selective effect on working memory in 40 patients with first episode of psychosis

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(Scoriels et al., 2012). Two studies found that modafinil did not improve cognitive abilities but was associated with limited improvement in negative symptoms (Kane et al., 2010; Bobo et al., 2011). Arbabi et al. (2012) also found a significant improvement effect on negative symptoms with eight weeks of 200 mg modafinil adjunctive treatment. Other studies, however, failed to show benefits of modafinil on cognitive or negative symptoms in schizophrenia. The effect of armodafinil, the R enantiomer of the racemic compound modafinil, on negative symptoms in a 4-week study by Kane et al. (2010) was not replicated in a later study with larger sample size and longer study period (24 weeks) by the same investigators (Kane et al., 2012). Pierre et al. (2007) found no effects on negative symptoms after eight weeks of modafinil treatment. Freudenreich et al. (2009) did not find any effects of modafinil on negative, cognitive, or wakefulness/fatigue symptoms in a study of 35 schizophrenia patients treated with clozapine. Sevy et al. (2005) found no treatment effects of modafinil on symptoms, fatigue, attention, working memory, or executive functioning in a study of 24 patients with schizophrenia. Two reviews, which were based on qualitative analysis rather than on meta-analysis, summarized the effects of modafinil on negative symptoms, cognitive, emotion, and fatigue in patients with schizophrenia, and concluded that there is little evidence on the effect on negative symptoms. However, because some studies reporting improvement in short-term memory, attention or emotional processing, these reviews called for further randomized and controlled studies to examine these specific effects (Saavedra-Velez et al., 2009; Scoriels et al., 2013). Therefore, the inconsistent results from reported studies, and the lack of enough qualified trials to perform meta-analysis as indicated in the review papers, suggest that the effects of modafinil in schizophrenia have still not been sufficiently explored. In addition to the possible treatment effects on negative symptoms, fatigue and cognitive impairment reviewed above, modafinil's efficacy in narcolepsy and sleep disordered breathing (SDB)-related excessive daytime sleepiness (EDS) (Keating and Raffin, 2005; Golicki et al., 2010) suggests that it may be helpful in patients with schizophrenia who also have EDS, a fairly common problem in this population (Jaffe et al., 2006). We therefore decided to assess the potential effects of modafinil on these four constellations of symptoms — EPS, EDS, negative and cognitive symptoms in patients with schizophrenia or schizoaffective disorder, although our primary focus was on the first two, which have not been addressed before. In order to test our hypotheses, only patients with prominent negative symptoms were included, and the randomization was stratified by presence or absence of EDS. 2. Patients and methods 2.1. Participants Participants were male patients aged 20 to 63 years with schizophrenia or schizoaffective disorder (DSM-IV criteria). Given the unknown effects of modafinil on prenatal development, women were not included. All patients were recruited from the UCSD Outpatient Psychiatric Services and the San Diego Veterans Affairs Medical Center. Inclusion criteria were: 18–65 years old; being able to communicate and give voluntary informed consent, and having an approved contact person for the duration of the study; a negative symptom score of ≥20 on the Positive and Negative Symptom Scale (PANSS); a score of N24 on the Folstein Mini-Mental State Exam (MMSE); on a stable dose of an SGAs; if on an antidepressant, anticholinergic, benzodiazepine and/or anticonvulsant, stable doses of these agents. Exclusion criteria were: current unstable medical illness or current or past clinical evidence of cerebral neurological impairment; history in the past two years or evidence in the past year of drug or alcohol abuse; diagnosis of narcolepsy; history of aggression. Uses of methylphenidate, amphetamines, pemoline, zolpidem, MAO inhibitors, anticoagulants, tricyclic antidepressants or barbiturates were not allowed during the study.

All patients signed an institutional review board approved consent form before being enrolled.

2.2. Study design This was a randomized, double-blind, placebo-controlled, adjunctive study. Modafinil was administered orally once a day for a total of eight weeks.

2.3. Assessments Parkinsonian (EPS) signs were assessed with the Simpson-Angus Scale for extrapyramidal side effects (SAS) (Simpson and Angus, 1970). A total score over 3 indicates minimal degree of EPS, and a total score over 6 indicates clinically significant degree of EPS. Other motor side effects were assessed with the Barnes Akathisia Rating Scale (BARS) (Barnes, 1989), and the Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976a). EDS was assessed with the Epworth Sleepiness Scale (ESS) (Johns, 1991). The self-administered ESS is a simple questionnaire to rate the likelihood of falling asleep in eight daytime situations. The range of ESS total score is 0–24, a total score of 8 or higher (Rosenthal and Dolan, 2008) was used as the cut-off score of EDS in the stratification of this study. Positive and negative symptoms were assessed with the PANSS (Kay et al., 1987), from which the total score and negative and positive scores were calculated. Illness severity was assessed with the Clinical Global Impressions-Severity (CGI-S) (Guy, 1976b). Cognitive abilities were assessed with a repeatable battery of neuropsychological (NP) tests which included seven tests: The Hopkins Verbal Learning Test–Revised (HVLT-R) (Brandt, 1991); Trail Making Test Part A and B (Reitan and Wolfson, 1998); the 64-card version of the Wisconsin Card Sorting Test (WCST-64) (Heaton, 1998); the Stroop Color and Word Test (Golden, 1978); the Letter (FAS) and Category (Animals) fluency test (Spreen and Strauss, 1998); the Digit Span, Digit Symbol, and Symbol Search subtests of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) (Wechsler, 1997); and the MMSE (Folstein et al., 1975). Four domains of cognitive abilities were covered by 12 subtests from these seven tests: episodic learning/memory; executive function; verbal and visual attention/working memory; psychomotor/mental processing speed (including a subtest of total words completed on the Color and Word trials of the Stroop Color and Word Test). Adverse events were determined by reports, laboratory tests, and vital signs.

2.4. Procedures After obtaining informed consent and determining eligibility, patients were randomly assigned into the modafinil or placebo group (1:1), and the randomization was stratified by EDS symptoms (total ESS score b 8 vs. ≥8), so patients in both groups would have similar degrees of EDS symptoms. The start of the study drug administration was on Day-0, and patients were followed up on Day-14, Day-28, Day-42, and Day-56. Data for rating scales were collected at these five time points; the NP test battery was administered on Day-0, Day-28 and Day-56; the CGI-S was assessed on Day-0. The beginning dose of modafinil on Day-0 was 50 mg, and was increased to 100 mg on Day-14 and 200 mg on Day-28, and continued at 200 mg for the remaining 4 weeks of the study. If subjects were unable to tolerate dosage increases, the dose was decreased accordingly.

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2.5. Statistical analysis Descriptive statistics (mean, standard deviation and standard error) were calculated for continuous variables; patient count and percentage were also provided. T-tests and Chi-squared tests or Fisher's exact tests were performed to check randomization balance between the treatment arms for key covariates, as well as for changes of PANSS score from Day-0 to the other four time points, and for adverse events. In order to place the NP test scores on a common metric, each raw subtest score was converted to a Z-score. Four domains' scores (mean of all subtests within the domain) and a composite score (the composition of the four domains' scores) were calculated. A larger composite or domain score indicates higher cognitive ability. A set of mixed model analyses was performed to assess the treatment effects of modafinil on EPS, EDS, negative symptoms, cognitive abilities and adverse effects. Treatment groups (arms), time, and group-x-time interaction were modeled as fixed effects. A significant group-x-time interaction would indicate that the changes in outcomes over time are different in the two treatment arms. All analyses were performed using version 9.3 of SAS (SAS Institute Inc.). All tests with P-values b 0.05 are reported as statistically significant. Given that four main outcomes (EPS, EDS, negative symptoms and NP composite score) were of interest, a Bonferroni correction would yield P b 0.0125 (0.05/4) as statistically significant, thus P = 0.0125 was set as the significance level for mixed model analyses of the main outcomes. 3. Results A total of 63 patients were screened and 24 were randomized (see Fig. 1). Comparisons of characteristics on Day-0 between the two groups

are listed in Table 1. Before the start of treatment, there were no significant differences between the two groups in demographics, use of anticholinergics (n%), illness severity (CGI-S), symptoms (PANSS), cognition (NP tests), EDS (ESS), parkinsonism (SAS) and adverse effects of neuroleptics (BARS and AIMS) (all P's N 0.1). The psychotropic medications for each patient and the CPZ equivalents of the antipsychotics are listed in Table 2. The CPZ equivalents were calculated using Andreasen's power transformation method (Andreasen et al., 2010). There was no significant difference between the two groups in the CPZ equivalents (P = 0.31).

3.1. EPS (parkinsonism) The prevalence of parkinsonian symptoms in all patients (n = 24) on Day-0 was 79.2% for minimal degree (total SAS score N 3) and 50% for clinically significant degree (total SAS score N 6). Fig. 2 shows the total SAS scores over the treatment period. There were no significant differences on Day-0 between the two groups (P = 0.35). There was a significant group-x-time interaction (P = 0.0054) for total SAS scores, i.e., total SAS scores decreased significantly in the modafinil group but remained unchanged in the placebo group. The total SAS scores decreased from Day-0 to Day-42 (P = 0.005) and from Day-0 to Day-56 (P = 0.0056) in the modafinil group, and these decreases were significantly greater than those in the placebo group. When the CPZ equivalents were added into the mixed model as a fixed effect for total SAS score, the CPZ's effect was not significant (P = 0.59), and the group-x-time interaction was still significant (P = 0.0055). These results indicate that compared to the placebo group, the modafinil group had significantly fewer parkinsonian signs and symptoms after eight weeks of treatment, with changes occurring

Screened (n= 63)

Not randomized (n= 39) Failed inclusion criteria: n=25 Met exclusion criteria: n=10 Withdraw consent: n=2 Lost follow-up: n=2

Randomized (n=24)

Placebo group (n=12)

Modafinil group (n=12)

Withdraw before Day 42 due to move (n=1)

Completed study (n=12)

Included in analysis (n=12)

291

Completed study (n=11)

Included in analysis (n=12)

Fig. 1. Patient's screening and enrollment flowchart.

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9

Table 1 Comparison of characteristics between treatment groups on Day-0. Modafinil (n = 12)

Age, mean (SD), y Ethnicity, N (%) Caucasian African-American Hispanic Education, mean (SD), y Marital, N (%) Single Married Duration of illness, mean (SD), y Use of anticholinergics, N (%) MMSE total score, mean (SD) Neuropsychological tests composite score, mean (SD) PANSS score, mean (SD) Total Positive Negative CGI-S score, mean (SD) ESS total score, mean (SD) SAS total score, mean (SD) BARS total score, mean (SD) AIMS total score, mean (SD)

47.8 (13.0)

48.5 (8.8)

8 (66.7) 3 (25.0) 1 (8.3) 12.1 (2.9)

9 (75.0) 2 (16.7) 1 (8.3) 12.4 (1.0)

Placebo

7

Placebo (n = 12)

SAS Score

Characteristic

Modafinil

8 6 5 4 3 2 1 0

9 (75.0) 3 (25.0) 14.5 (9.7) 3 (25.0) 28.8 (0.8) 0.063 (0.726)

8 (66.7) 4 (33.3) 19.8 (8.5) 4 (33.3) 28.8 (1.2) −0.097 (0.730)

78.1 (7.7) 16.7 (4.6) 25.6 (2.5) 4.0 (0.0) 7.0 (5.5) 7.3 (3.8) 2.3 (2.3) 4.3 (5.8)

77.2 (9.3) 15.2 (4.0) 26.0 (3.7) 4.2 (0.4) 8.4 (5.8) 5.6 (4.8) 1.5 (1.7) 3.0 (2.6)

primarily during the last two weeks of therapy, and these changes were not related to the doses of antipsychotics.

3.2. Excessive daytime sleepiness (EDS) On Day-0, 5 of the 12 patients (41.7%) in the modafinil group and 6 of the 12 patients (50.0%) in the placebo group had a total ESS score of ≥8; the difference between the two groups was not significant (P = 0.68). There was no significant overall time effect (P = 0.63) and no significant group-x-time interaction (P = 0.57) for the total ESS scores; i.e., modafinil did not show any significant effects on EDS.

Day-0

Day-14

Day-28

Day-42

Day-56

Fig. 2. Comparison of SAS total scores (mean, standard error) between treatment groups over time. There was a significant group-x-time interaction (P = 0.0054). SAS = Simpson-Angus Scale.

3.3. Positive and negative symptoms The PANSS total, positive and negative scores are shown in Fig. 3. There was an overall time effect for the total (P = 0.0005) and negative (P b 0.0001) scores, but no significant group-x-time interactions for the total (P = 0.43), positive (P = 0.92) or negative (P = 0.65) scores; i.e., the total and negative scores of PANSS decreased significantly in both groups after 8 weeks of treatment. As seen in Fig. 3, the changes in the total PANSS scores were driven by the changes in the negative scores. Although there was no significant group-x-time interaction, the decreases of negative scores in the modafinil group were all greater than that in the placebo group from Day-0 to Day-14 (1.0 ± 1.7 vs. 0.6 ± 1.0), to Day-28 (2.1 ± 2.3 vs. 1.0 ± 1.9), to Day-42 (2.9 ± 3.0 vs. 1.1 ± 2.3) and to Day-56 (3.3 ± 3.3 vs. 2.0 ± 2.8). 3.4. Cognitive abilities As shown in Fig. 4, there were no significant group-x-time interactions for the NP composite score (P = 0.99) and the four domain scores (all P's N 0.4). There was, however, a significant overall time effect for the psychomotor/mental processing speed domain (P = 0.011), i.e., both groups improved after 8 weeks of study. Examination of the

Table 2 Psychotropic medication regimens for both groups. Patient/group

Antipsychotics

CPZ equivalentsa

Anticholinergics

Other agents

Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Modafinil Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo

Risperidone Risperidone Risperidone Olanzapine Quetiapine Clozapine, risperidone Risperidone Risperidone Perphenazine, ziprasidone Quetiapine Olanzapine Aripiprazole Risperidone Olanzapine, haloperidol Risperidone, haloperidol Risperidone Quetiapine, clozapine Quetiapine, perphenazine Risperidone Risperidone Aripiprazole Risperidone Risperidone Aripiprazole

326.9 72.9 692.1 525.0 761.1 535.9 239.4 326.9 557.7 761.1 106.7 907.8 692.1 630.0 562.3 692.1 426.0 265.5 692.1 786.2 907.8 326.9 507.0 508.6

Benztropine

Fluoxetine, mirtazapine, lorazepam Fluoxetine Citalopram, valproate semisodium, gabapentin, temazepam Fluoxetine, valproate semisodium, lorazepam Sertraline, diphenhydramine Citalopram, clonazepam diphenhydramine, Clonazepam Lorazepam Trazodone, bupropion, clonazepam Trazodone, lorazepam

a

Calculated using Andreasen's power transformation method.

Trihexyphenidyl Benztropine

Trihexyphenidyl Benztropine Trihexyphenidyl

Citalopram, trazodone, lorazepam Fluoxetine, buspirone, clonazepam Fluoxetine Citalopram, lorazepam Trazodone, mirtazapine Sertraline, valproate semisodium Clonazepam Fluoxetine

Ipratropium bromide, benztropine Clonazepam Bupropion Diphenhydramine

J.B. Lohr et al. / Schizophrenia Research 150 (2013) 289–296

0.4

85

80

75

70

Placebo

0.3 0.2 0.1 0 -0.1 -0.2

Day-28

Day-42

Day-56

20 Modafinil

Placebo

18 16 14 12 10 Day-14

Day-28

Day-42

Day-56

NP Executive Function Score

Day-0 28

Modafinil

Placebo

26

24

22

20 Day-0

Day-14

Day-28

Day-42

Day-56

Fig. 3. Comparison of PANSS total, positive and negative scores (mean, standard error) between treatment groups over time. There was a significant time effect for the total and negative (both P's b 0.0005) scores, but no significant group-x-time interactions for all three scores (all P's N 0.4). PANSS = Positive and Negative Syndrome Scale.

individual subtests in this domain showed that the increase of the Z-score in the completed word trial of the Stroop Color and Word Test was significantly higher in the modafinil group than that in the placebo group on Day-28 (P = 0.037), but not on Day-56 (P = 0.52). 3.5. Tolerability Modafinil was generally well-tolerated. One patient in the modafinil group displayed increased paranoia/irritability on Day-42, this problem resolved in two weeks after reducing the modafinil dosage from 200 mg to 150 mg. One patient in the placebo group had worsening of delusions. Neck/back/hip pain, heartburn, diarrhea, skin rash or hypotension were observed in one or two patients in the modafinil group, but the rates were not significantly different from that in the placebo group (all P's N 0.1). The sitting diastolic and standing systolic blood pressure (BP) values were higher in the modafinil group than in the placebo group (group-xtime interaction P = 0.023, P = 0.013 respectively), but at no time were the BP values in an abnormal range, thus these changes of BP were not considered to be clinically meaningful. There were no other significant differences between the two groups in body temperature or heart rate readings. No notable abnormalities were observed in the laboratory tests. No significant differences between the two groups in other motor side effect as indicated by total BARS and AIMS scores (both P's N 0.7).

NP Attention Working Memory Score

Day-14

NP Processing Speed Score

Day-0

NP Episodic Learning Memory Score

65

PANSS Positive Score

Modafinil

Placebo

NP Composite Score

PANSS Total Score

Modafinil

PANSS Negative Score

293

Day-0

Day-28

Day-56

0.6 Modafinil

Placebo

0.5 0.4 0.3 0.2 0.1 0 -0.1 -0.2 Day-0 0.4

Day-28 Modafinil

Day-56

Placebo

0.3 0.2 0.1 0 -0.1 -0.2 -0.3 Day-0 0.8

Day-28 Modafinil

Day-56

Placebo

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 -0.1 Day-0 0.6

Day-28 Modafinil

Day-56 Placebo

0.5 0.4 0.3 0.2 0.1 0 -0.1 -0.2 Day-0

Day-28

Day-56

Fig. 4. Comparison of NP composite and domain scores (mean, standard error) between treatment groups over time. No significant group-x-time interactions for the composite and four domain scores (P's all N 0.4). There was an overall time effect for the NP processing speed domain scores for both groups (P = 0.011). NP = neuropsychological. Larger scores indicate higher cognitive abilities.

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4. Discussion In this study, we found a substantial improvement in parkinsonism as measured by the Simpson-Angus Scale (SAS). Patients treated with modafinil demonstrated a greater reduction in total SAS scores in comparison with patients who received placebo. However, we did not find any evidence that excessive daytime sleepiness was improved, nor strong evidence that modafinil treatment improved positive or negative symptoms or cognitive abilities in schizophrenia. Motor symptoms are common in both treated and never-treated patients with schizophrenia, and parkinsonism is the most commonly observed motor dysfunction, found in about one fourth of first episode and never-treated schizophrenic patients, and one fourth to a half of those chronically medicated (Walther and Strik, 2012). The severity of pre-treatment and antipsychotic-induced parkinsonian symptoms is correlated and the latter can be predicted by the former (Caligiuri and Lohr, 1997). The present study found a 50% prevalence of significant parkinsonism in both groups before the start of modafinil treatment, which is consistent with that reported in the literature (Walther and Strik, 2012). Mixed model analysis revealed that modafinil significantly reduced parkinsonian symptoms after eight weeks of treatment. This is the first study to report a therapeutic effect of modafinil on parkinsonism in medicated patients with schizophrenia or schizoaffective disorder. Parkinsonism in treated patients with schizophrenia is generally considered as the consequence of decreased dopaminergic function in the striatum caused by antipsychotics. The pathophysiology of parkinsonism in never-treated patients is unknown, but may also involve dopaminergic mechanisms (Caligiuri et al., 1993; Susatia and Fernandez, 2009). There is evidence that dopamine receptors mediate the modafinil effects on waking, exploratory and hyperactivity behaviors (Minzenberg and Carter, 2008; Mitchell et al., 2008; Young et al., 2011), and also evidence that modafinil blocks dopamine transporters and increases dopamine in the human brain (Volkow et al., 2009). In general, the mechanism of action of modafinil is still not clear, and appears to involve a number of complex effects, including effects on hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate systems (Ballon and Feifel, 2006). There is evidence of enhancement of serotonergic transmission (Ferraro et al., 2002), and evidence that noradrenergic systems may be involved as well (Minzenberg and Carter, 2008; Mitchell et al., 2008; Young et al., 2011). There is other evidence that modafinil may be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of parkinsonism (Xiao et al., 2004). Results suggest that modafinil may also be neuroprotective through antioxidant effects (Gerrard and Malcolm, 2007). Therefore, although it is possible that the beneficial effect we observed of modafinil on parkinsonism occurs via the dopaminergic system, other possible mechanisms, including indirect effects of other neurotransmitters on the motor system, or neuroprotective effects may also be involved. Another possible explanation of the modafinil's effect on parkinsonism is its effects on the hepatic cytochrome P450 (CYP) enzymes system. It has been reported that modafinil is an inducer of some type of CYP, such as the CYP3A4 (Darwish et al., 2008), and the CYP3A4 is involved in the metabolism of atypical antipsychotics (Urichuk et al., 2008), it is then possible that modafinil decreased the drug plasma concentrations, thus decreasing the levels of parkinsonism. However, the lack of significant difference of the CPZ equivalents between the two groups, the lack of associations between the CPZ equivalents and total SAS scores, and the stable positive symptoms throughout the process of the study in all patients do not support this hypothesis. The lack of significant findings about the overall effects of modafinil on negative symptoms and cognitive abilities in this study is consistent with the findings from other investigators (Sevy et al., 2005; Pierre et al., 2007; Freudenreich et al., 2009; Bobo et al., 2011), who did not find

beneficial effects of modafinil on either negative symptoms or cognitive abilities. These negative findings could indicate that those antipsychotics and other agents possibly mitigated modafinil's effects on monoamine function and cognition, but again, the lack of significant group differences in CPZ equivalents, positive symptoms and overall cognition do not suggest these effects. The finding of improvement in the scores of processing speed domain of cognition in both groups may suggest a practice effect, although it could also be an effect of the second generation antipsychotic medications which all patients received, as noted in a review by Morrens et.al. (Morrens et al., 2007), in which the authors concluded that atypical agents produce modest improvements in psychomotor slowing (processing speed). The current study also identified a significant group difference on Day-28 in the Stroop Word Test, which suggests an effect of modafinil on the processing speed domain of cognition, but this same effect could not be detected at the end of study (Day-56), indicating at best a short-term effect of modafinil on the processing speed, if any. Given the above findings from the current study and studies by others, it is unclear if the group-x-time interactions for both negative symptoms and cognition would become statistically significant if the sample size were increased and the study time were extended. Modafinil has been approved by the FDA to be used in the treatment of EDS, which is usually associated with narcolepsy and SDB (Keating and Raffin, 2005; Golicki et al., 2010). However, this current study, together with other studies in which the EDS symptoms were assessed (Freudenreich et al., 2009; Kane et al., 2010), failed to show a beneficial effect on EDS in patients with schizophrenia. The reasons for this are not clear, although it is possible that EDS symptoms in patients with schizophrenia may occur through a different mechanism. In our sample, although an attempt was made to find subjects with EDS, the ESS scores were not as severe as is usually seen in patients with narcolepsy or SDB, which may have also reduced the chance of finding evidence for an effect on EDS. One important concern of modafinil treatment in schizophrenia and schizoaffective disorder is exacerbation of psychopathology, as there have been reports of mania or hypomania following treatment (Wolf et al., 2006; Plante, 2008), as well as reports of psychosis or exacerbation of psychosis (Narendran et al., 2002; Wu et al., 2008). However, the present study did not find any compelling evidence of these phenomena in the modafinil group, and the positive scores of the PANSS also remained at the same level. Except for the slight increase in blood pressure, no other adverse effects were observed in the modafinil group compared to placebo group, indicating that for our sample modafinil was a safe treatment. There are several caveats to be kept in mind in interpreting the results of this study. First, because our study was only eight weeks in length, and the modafinil dose of 200 mg/day only lasted for four weeks, we would have missed any therapeutic benefit which requires either very long periods of treatment, or larger doses, or both. Second, cognitive symptoms are a complex set of phenomena, and it is very difficult to rule out factors such as tools not sensitive enough to detect the improvements. Third, the sample size was quite modest, and it might not have provided enough power to detect all possible effects of modafinil on cognition and negative symptoms, given that small trends were observed in this study (greater increases of one NP subtest score on Day-28, and greater decreases of negative scores in the modafinil group at all treatment time points). Also with this limited sample size, we could not determine if modafinil may be beneficial on hyperkinesias, such as tardive dyskinesia, and this may also be worth studying further, considering the observed benefit on parkinsonism. In summary, eight weeks of modafinil treatment with up to 200 mg/day was safe, and demonstrated a significant improvement effect in parkinsonian symptoms. Although the modafinil treated group also showed signs of small improvement in the processing speed domain of cognitive abilities and in negative symptoms, these effects were not all statistically significant. Considering the likely practice

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effect on cognitive tests and diminished symptom score over time, further double-blinded, placebo-controlled studies in larger samples and with longer treatment durations, and employing more sensitive and more specific neuropsychological testing tools, are still warranted in order to test these effects of modafinil. The potential of a beneficial effect of modafinil on parkinsonism also requires follow-up with larger scale studies, and possibly with other disorders, such as idiopathic Parkinson's Disease, Huntington's Disease, and other motor problems. Role of funding source This study was an investigator-initiated trial sponsored by the modafinil manufacturer, Cephalon Inc. Except for funding from the manufacturer and income from our primary employers, additional salary support was provided by the VA Center of Excellence for Stress and Mental Health (CESAMH) for JBL, LL, TAM, JDM, and SAI. Contributors JBL, MPC and SAI designed the study and wrote the protocol. TPK, TMD and JDM coordinated/conducted the study and managed the literature search analyses. LL undertook the statistical analysis and helped JBL writing the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest During the past 3 years Dr. Ancoli-Israel serves on the advisory board or acts as a consultant for Astra Zeneca, Ferring Pharmaceuticals Inc., GlaxoSmithKline, Hypnocore, Johnson & Johnson, Merck, NeuroVigil, Inc., Orphagen Pharmaceuticals, Pfizer, Philips, Purdue Pharma LP, and sanofi-aventis. Acknowledgments We would like to thank Ms. Heather Donovan for her excellent administrative assistance to this study.

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