Participants

Right-handed males aged 18-60 years, with premorbid IQ >70 on the National Adult Reading Test (NART; Reference Nelson and O'ConnellNelson & O'Connell, 1978) and a DSM-IV (American Psychiatric Association, 1994) diagnosis of schizophrenia and prominent negative symptomatology (rating 3 on at least one item of the Scale for the Assessment of Negative Symptoms (SANS); Reference AndreasenAndreasen, 1983) were included. Exclusion criteria were: prominent ‘positive' symptomatology (marked delusions and/or hallucinations); recent history of mental state instability; changes to psychotropic medication or admission to hospital within 3 months of assessment; significant history of neurological, endocrine or cardiovascular disorder; hypersensitivity to modafinil; concurrent prescription of other stimulant medication; concurrent substance misuse; and contraindications to magnetic resonance imaging scanning (metallic implants, foreign bodies and claustrophobia).

Thirty-two patients were approached and 21 agreed to participate following a full explanation of the study. Nineteen of these satisfied detailed assessment of the inclusion and exclusion criteria. Participants underwent psychiatric (Brief Psychiatric Rating Scale; Reference Overall and GorhamOverall & Gorham, 1962; SANS; Scale for the Assessment of Positive Symptoms; Reference AndreasenAndreasen, 1984; Beck Depression Inventory; Reference Beck, Ward and MendelsonBeck et al, 1961; Mini-Mental State Examination; Reference Folstein, Folstein and McHughFolstein et al, 1975), physical (including an electrocardiogram) and neuropsychological assessment (Simpson-Angus Scale; Reference Simpson and AngusSimpson & Angus, 1970; Abnormal Involuntary Movements Scale; Reference GuyGuy, 1976; Barnes Akathisia Scale; Reference BarnesBarnes, 1989).

Written informed consent was obtained from each patient. The study was approved by the North and South Sheffield Research Ethics Committees, and also the Rotherham and the Doncaster and South Humber Research Ethics Committees. Because the study was funded by an ‘investigator-led award' and was not a ‘company-sponsored trial', research indemnity was provided by the Sheffield Care Trust (and reciprocally participating National Health Service trusts) and clinical trial insurance was provided by the University of Sheffield.

Procedures

We utilised a randomised, double-blind placebo-controlled crossover design. Patients were studied on 2 days, 1 week apart. On each day, patients received oral modafinil (100 mg) or placebo 2 h prior to functional magnetic resonance imaging (fMRI) scanning. Administration and scanning times were predicated on the drug's pharmacokinetics in humans; peak plasma levels occur 2-4 h post-acute oral dosing (Cephalon, 1999; Reference Robertson and HellriegelRobertson & Hellriegel, 2003). Randomisation, performed by a pharmacist (not a member of the research team), was achieved by drawing labelled counters; this ensured that approximately equivalent numbers of patients received modafinil and placebo on day 1, and vice versa on day 2. Patients were required not to smoke or consume caffeine prior to scanning. They were admitted for 24-h observation after the scanning procedure. The outcome measures were: a difference in fMRI signal, during a working memory task, between the modafinil and placebo conditions; a difference in behavioural performance (accuracy), during the same intra-scanner task, between modafinil and placebo conditions; and a patient-wise bivariate correlation between the first two measures.

Adverse events and image quality

We analysed data from 17 of the 19 patients entering the study. One patient did not complete the study due to relapse of acute psychosis 4 days after the first scanning day. Ethical considerations required disclosure of his randomisation status, revealing that he had received modafinil. This was the only clinically significant adverse event that occurred during the study. Data from another patient could not be analysed because of technical problems with his second-session fMRI images.

Demographic data

Patients were predominantly middle-aged males who had been ill for approximately 15 years (Table 1). Sixteen were single; none was in paid employment but five performed voluntary work; 16 received maximum disability living allowance; eight lived in their ‘own' accommodation; three with parents, two in supported group projects and four in rehabilitation units. Most patients were receiving oral antipsychotics (n=13), which were ‘atypical' in all but one case. Four patients received intramuscular (‘typical') depot medication. Of these 17 patients, none changed medication during the study period. Nine patients received modafinil on day 1 and placebo on day 2; eight received the reverse.

Table 1

Demographic and clinical characteristics of included patients

	Mean (maximum possible)	s.d.
Age (years)	37.7	9.5
Years of education	10.9	2.7
IQ	104.8	9.4
Edinburgh Handedness Inventory	100% right-handed	0
Clinical features
Duration of illness (years)	14.8	10.1
Brief Psychiatric Rating Scale	55.2 (112)	10.5
Scale for the Assessment of Negative Symptoms	11.5 (25)	2.2
Scale for the Assessment of Positive Symptoms	3.6 (20)	2.1
Beck Depression Inventory	10.3 (63)	10.7
Mini-Mental State Examination	29.3 (30)	0.6
Extrapyramidal side-effects
Simpson-Angus Scale	6.1 (40)	8.5
Abnormal Involuntary Movements Scale	2.3 (40)	3.2
Barnes Akathisia Scale	1.9 (14)	2.6

Behavioural measures

Statistical comparisons were prespecified, except where indicated. We used non-parametric tests to analyse the group behavioural (accuracy) data during the working memory task under placebo and modafinil conditions (these were not normally distributed). Under placebo conditions, response accuracy for the control ‘0-back' condition was 19-88% (median 71%) and did not differ significantly from that on modafinil: range 11-99%, median 71% (Wilcoxon signed rank test; Z=0.12; P=0.91). Under placebo conditions, response accuracy for the ‘2-back' task was 5-85% (median 26%) and did not differ significantly from that on modafinil: range 4-79%, median 22% (Wilcoxon signed rank test; Z=0.97; P=0.33).

Brain activations

Functional image analysis showed that on both the modafinil and placebo days the patients exhibited activations during the 2-back condition (relative to the 0-back) in predicted brain regions (Tables 2 and 3), specifically the prefrontal, anterior cingulate and parietal cortices (Callicott et al, Reference Callicott, Bertolino and Mattay2000, Reference Callicott, Egan and Mattay2003; Reference Meyer-Lindenberg, Poline and KohnMeyer-Lindenberg et al, 2001).

Table 2

Brain areas exhibiting greater activation during working memory than baseline under placebo condition

Region (Brodmann area)	Coordinates (x,y,z)	Z	Voxels
Left middle frontal gyrus (9/46)	− 50, 32, 21	3.56	159
Left middle/superior frontal gyrus (6/8)	− 26, 24, 54	3.42	151
Anterior cingulate gyrus (32)	0, 22, 45	3.90	173
Right inferior frontal gyrus (47)	50, 17, −9	3.99	132
Right middle frontal gyrus (6)	36, 3, 57	3.67	149
Left inferior parietal lobule (40)	− 48, −45, 41	3.63	135
Right inferior parietal lobule (40)	42, −50, 54	4.10	194
Right posterior parietal cortex (7/19/40)	34, −66, 36	4.23	172
Right cerebellar hemisphere	38, −71, −28	3.27	101

Activations exceeding statistical threshold P < 0.01, uncorrected, for height and extent of activation are shown; stereotactic coordinates are in the standard space of Talairach & Tournoux (1988); ‘Z' reflects peak statistical ‘height' of the most activated voxel in each cluster; ‘voxels' indicates total number of voxels exceeding height threshold P < 0.01 in each cluster.

Table 3

Brain areas exhibiting greater activation during working memory than baseline under modafinil condition

Region (Brodmann area)	Coordinates (x, y, z)	Z	Voxels
Left inferior/middle frontal gyrus (44/10)	− 38, 52, 1	4.36	502
Right anterior cingulate gyrus (32)	6, 38, 18	3.79	50 1
Right inferior frontal gyrus (47)	38, 23, −11	4.14	305
Right middle/superior frontal gyrus (6/8)	34, 10, 51	5.27	6165 2
Right anterior cingulate/medial frontal gyrus (32/8)	4, 27, 35	5.25	2
Left inferior frontal gyrus (47)	− 30, 21, −3	4.85	2
Left posterior parietal cortex (19)	− 28, −68, 42	5.03	4439 2
Left precuneus (7)	− 6, −65, 51	4.56	2
Right posterior parietal cortex (19)	32, −64, 33	4.49	2
Right cerebellar vermis	10, −83, −21	4.08	145
Right cerebellar hemisphere	36, −69, −25	3.89	305
Left cerebellar hemisphere	− 30, −62, −30	3.82	176

Activations exceeding statistical thershold P <0.01, uncorrected, for height and extent of activation are shown; stereotactic coordinates are in the standard space of Talairach & Tournoux (1988); ‘Z' reflects peak statistical ‘height' of the most activated voxel in each cluster; ‘voxels' indicates total number of voxels exceeding height threshold P <0.01 in each cluster.

1. Although not significant for extent of activation in the modafinil-only analysis, this distinct area of anterior cingulate cortex activation represents the region of ‘most difference' between modafinil and placebo conditions and, hence, corresponds to the basis for the activation observed in the main modafinil v. placebo contrast (the coordinates were also used to define a region of interest within which correction for multiple comparisons was performed; see text and Fig. 1).

2. Large clusters and their anatomically distinct foci.

Functional image analysis comparing the modafinil with the placebo condition revealed that working memory task performance was associated with significantly greater activation solely in the anterior cingulate cortex (Fig. 1; Talairach coordinates: x=6 mm, y=38 mm, z=15 mm; 131 supra-threshold voxels; peak Z score=3.14; P<0.01, uncorrected, for height and extent of activation). This activation remained significant after correction for multiple comparisons within the defined region of interest (P<0.05). Examining the separate modafinil and placebo brain maps (of the working memory v. baseline contrast) confirmed that this focal difference was due to greater anterior cingulate cortex activation during working memory than baseline performance on modafinil (x=6 mm, y=38 mm, z=18 mm; 50 voxels; Z=3.79; P<0.01, uncorrected, for height of activation), and not the converse, namely, greater activation during baseline than working memory on placebo.

Fig. 1

The brain area (anterior cingulate cortex) that exhibited greater activation during a working memory task on modafinil than on placebo. Group data displayed against a ‘canonical' T₁-weighted image (upper panels); supra-threshold voxels are shown in yellow (P<0.01). In order to demonstrate the regional specificity of this finding the data are also displayed at the same statistical threshold within a ‘glass brain' (lower panels).

Patient-wise differences in anterior cingulate cortex activation (Fig. 1) and behavioural performance (between modafinil and placebo conditions) were positively and significantly correlated (Fig. 2; Spearman's ρ=0.42; one-tailed P<0.05). However, this correlation did not reflect a straightforward relationship between improved activation and improved performance. Rather, it reflected an increased fMRI signal in the majority of patients during the modafinil session, with concomitant improvement of memory performance in half and a decreased signal in a minority of patients (in response to modafinil), most of whom exhibited reduced performance on the drug (Fig. 2). Hence, for the patient group as a whole there was a relationship between the degree to which anterior cingulate cortex activation, during the memory task, was modulated (increased/decreased) by the drug and their level of cognitive performance. Although a subgroup of patients exhibited enhanced cognition (in association with increased anterior cingulate cortex activation), no patient exhibiting reduced anterior cingulate cortex activity improved cognitively.

Post hoc examination of the data revealed that of the five patients exhibiting improvements of both anterior cingulate cortex fMRI signal and 2-back performance, four were receiving ‘typical' neuroleptics (depot or sulpiride) and one was receiving olanzapine. That is, of five patients who received ‘typicals' the majority responded positively to modafinil (both physiologically and cognitively). Conversely, of 12 patients receiving ‘atypicals' only one exhibited this pattern. Moreover, a post hoc analysis confirmed that the positive correlation between anterior cingulate cortex signal and performance change was most significant in the five patients receiving ‘typical' antipsychotics (Spearman's ρ=1.00, P not calculated). Conversely, when these patients were excluded from the group analysis, the latter was no longer significant (for 12 patients receiving ‘atypicals', ρ=0.03; one-tailed P=0.47). Exclusion of those subjects whose performance was at the level of chance on placebo led to exclusion of three of the four subjects receiving depots and a reduction of the anterior cingulate cortex/performance correlation to trend significance (ρ=0.58; one-tailed P=0.06). Hence, it is possible that those receiving depot medication derived the greatest benefit from modafinil (perhaps as a consequence of greater initial deficit) and contributed most to the findings.

Fig. 2

Modafinil v. placebo in a working memory task: correlation between difference in anterior cingulate activation and behavioural performance. For each patient (n=17) the x-axis shows difference in accuracy during an intra-scanner working memory task between modafinil and placebo conditions; the y-axis shows the corresponding difference in estimated functional magnetic resonance imaging (fMRI) signal change. Positive values indicate greater accuracy/greater fMRI signal change on modafinil than on placebo.

We further investigated this post hoc ‘deficit/benefit' hypothesis and found that those exhibiting improved working memory performance on modafinil had demonstrated significantly worse performance on a verbal fluency task at initial assessment compared with other patients. Responders generated 7-18 words in 1 min (median 10); non-responders generated 4-25 words, median 11.5 (Mann-Whitney U-test; Z=2.19; P=0.03). There were no correlations between intra-scanner working memory task performance and specific symptom ratings.

Finally, by way of validating our sample against those described in successive reports, which have repeatedly described positive correlations between 2-back accuracy and right dorsolateral prefrontal cortex activity in people with schizophrenia compared with ‘normals' (Callicott et al, Reference Callicott, Mattay and Bertolino1999, Reference Callicott, Bertolino and Mattay2000), we examined the correlates of performance per se on the 2-back task. We found the right dorsolateral prefrontal cortex implicated under both conditions (placebo; x=44 mm, y=41 mm, z=9 mm, 21 voxels, Z=2.75, P<0.01, uncorrected, for height of activation; modafinil: x=44 mm, y=49 mm, z=18 mm, 62 voxels, Z=3.15, P<0.01, uncorrected, for height of activation).

Neural response

We administered a single low dose of modafinil to people with chronic schizophrenia and assessed working memory during fMRI. Our data reveal a specific effect of the drug upon an area of the frontal lobe called the anterior cingulate cortex. Importantly, this effect was specific to the active memory condition and not the baseline state. Anterior cingulate cortex is involved in a wide range of executive functions (Reference Bush, Luu and PosnerBush et al, 2000) and has been activated during working memory protocols in previous studies (Callicott et al, Reference Callicott, Bertolino and Mattay2000, Reference Callicott, Egan and Mattay2003; Reference Meyer-Lindenberg, Poline and KohnMeyer-Lindenberg et al, 2001). Its activation in people with chronic schizophrenia appears to be enhanced by modafinil (Fig. 1).

Cognitive response

Despite enhanced anterior cingulate cortex activation at the group level (during working memory performance), most of our patients did not exhibit enhanced cognition. For the group as a whole there was no effect of modafinil upon working memory (on this protocol). Therefore it might be posited that increased anterior cingulate cortex activation is either unrelated to cognition or indicative of reduced efficiency of cognitive processing (Reference Callicott, Bertolino and MattayCallicott et al, 2000; Reference ManoachManoach, 2003). If greater anterior cingulate cortex activation occurs without an increase in cognitive performance then brain function might be said to be less efficient in the presence of modafinil. However, it is important to note that cognitive function did improve in a minority of patients, and that although it might be posited that this is to be expected statistically (as merely a manifestation of variation around the mean), there is a feature of the data that runs counter to this interpretation. This is the positive correlation between anterior cingulate cortex activation and cognitive improvement (Fig. 2). If modafinil simply made anterior cingulate cortex function less efficient, then we should expect such a correlation to be negative. The positive correlation implies that the magnitude of anterior cingulate cortex activation and cognitive performance are indeed related in the context of modafinil exposure; those exhibiting the greater anterior cingulate cortex response also exhibit the greater cognitive enhancement (of working memory).

Accounting for ‘responders'

It is of interest that those exhibiting greater physiological and cognitive response to modafinil tended to be those who were receiving ‘typical' neuroleptic medications (depots and sulpiride). The numbers are small but there may be a rationale for this finding. The neurotransmitter systems implicated in the promotion of wakefulness by modafinil include the dopaminergic and serotonergic systems. Although antipsychotics share antagonism of the dopaminergic system (especially at the D2 receptor), the typicals and atypicals differ in their affinities for other receptors, particularly 5HT_2A (Reference Keefe, Silva and PerkinsKeefe et al, 1999). In animal models modafinil's effect of increasing alertness is attenuated by 5HT_2A antagonism (Reference Shelton, Nishino and VaughtShelton et al, 1995), hence, it is possible that atypical antipsychotic treatment (if antagonising 5HT_2A) might constrain the cognotropic effects of modafinil (a hypothesis deserving further study). Alternatively, the ability of atypicals themselves to enhance cognition (albeit to a limited extent; Reference Keefe, Silva and PerkinsKeefe et al, 1999) might curtail further improvement (on modafinil).

Safety

There are a number of caveats to our study and its findings. First, for the reasons described, we deliberately utilised a relatively low dose of modafinil. This may have been sub-optimal. Nevertheless, one of our participants underwent psychotic relapse 4 days post-drug. We cannot determine whether modafinil was responsible. Although covert non-adherence to concurrent medication cannot be excluded (he was receiving an oral antipsychotic), we must be wary of seeking to exculpate the test medication. However, a psychotic reaction to a single dose of modafinil is unprecedented (to our knowledge), although there are cases of psychosis emerging de novo in those receiving multiple doses. The manufacturer's prescribing information reports that: ‘one healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of [modafinil] and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.' (Cephalon, 1999). The British National Formulary does not mention psychosis as either a contraindication to or a consequence of modafinil exposure.

In a recent study of 20 patients with schizophrenia exposed to a single dose of 200 mg of modafinil, the drug elicited no exacerbation of psychosis (Reference Turner, Clark and Pomarol-ClotetTurner et al, 2004). However, there are anecdotal accounts of schizophrenic relapse following repeated dosing (Reference Narendran, Young and ValentiNarendran et al, 2002; Reference Rosenthal and BryantRosenthal & Bryant, 2003). Further multi-dosing studies in other centres may help to clarify the magnitude of such a putative risk.

CLINICAL IMPLICATIONS

1. ▪ Schizophrenia is associated with cognitive impairments that have an impact upon social function; a cognitive enhancer such as modafinil might reduce such impairments.

2. ▪ Patients with chronic schizophrenia exhibited increased anterior cingulate activation in response to modafinil while performing a working memory protocol; some also exhibited improved memory performance.

3. ▪ Of the patients exhibiting improved memory performance on modafinil, most were receiving concomitant ‘typical' antipsychotic medication.

LIMITATIONS

1. ▪ As in many neuroimaging studies, the number of subjects examined is relatively small.

2. ▪ The impact of memory improvement upon day-to-day function (outside the scanner) remains to be demonstrated.

3. ▪ Those patients who may derive cognitive benefit from modafinil require further characterisation.