Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury

ABSTRACT

Objective: Prolonged mental fatigue and cognitive impairments are common after a mild traumatic brain injury (TBI). This sets limits for rehabilitation and for regaining the capacity for work and participation in social life.

Method: This follow-up study, over a period of approximately 5.5 years was designed to evaluate the effect and safety of methylphenidate treatment for mental fatigue after a mild TBI. A comparison was made between those who had continued, and those who had discontinued the treatment. The effect was also evaluated after a four-week treatment break.

Results: Significant improvement in mental fatigue, depression, and anxiety for the group treated with methylphenidate (p < .001) was found, while no significant change was found for the group without methylphenidate. The methylphenidate treatment group also improved their processing speed (p = .008). Withdrawal produced a pronounced and significant deterioration in mental fatigue, depression, and anxiety and a slower processing speed. This indicates that the methylphenidate effect is reversible if discontinued and that continued methylphenidate treatment can be a prerequisite for long-term improvement. The effect was found to be stable and safe over the years.

Conclusion: We suggest methylphenidate to be a possible treatment option for patients with post-TBI symptoms including mental fatigue and cognitive symptoms.

KEYWORDS:

• Methylphenidate
• mild TBI
• mental fatigue
• cognition

Introduction

Long-term mental fatigue and cognitive impairment are common after a mild, moderate or severe traumatic brain injury (TBI) and these can have a significant impact on work, well-being and quality of life (1). Fatigue and concentration deficits are acknowledged as being one of the most distressing and long-lasting symptoms following mild TBI (1). There is currently no approved treatment (2), although the most widely used research drug for cognitive impairments after TBI is methylphenidate (3). A few studies have used methylphenidate for mental fatigue after TBI with promising results including our own (4,5). Other clinical trials of drugs have reported improvements in mental fatigue ((−)-osu6162 (6)) or none ((−)-osu616, modafinil (7–9)).

In our feasibility study of methylphenidate (not placebo controlled) we reported decreased mental fatigue, improved processing speed and enhanced well-being with a “normal” dose of methylphenidate compared to no methylphenidate for people suffering from post-traumatic brain injury symptoms (4). We tested methylphenidate in two different dosages and found that the higher dose (20 mg three times/day) had the better effect compared to the lower dose. We also found methylphenidate to be well tolerated by 80% of the participants. Adverse events were reported as mild and the most commonly reported side-effects included restlessness, anxiety, headache, and increased heart rate; no dependence or misuse were detected (10). However, a careful monitoring for adverse effects is needed, as many patients with TBI are sensitive to psychotropic medications (11).

Participants who experienced a positive effect with methylphenidate were allowed to continue the treatment. We have reported the long-term positive effects on mental fatigue and processing speed after 6 months (12) and 2 years (13). No serious adverse events were reported (13)(Figure 1). In a 30-week double-blind-randomized placebo-controlled trial, Zhang et al. reported that methylphenidate decreased mental fatigue and improved cognitive function in the participants who had suffered a TBI. Moreover, social and rehabilitation capacity and well-being were improved (5). Other studies evaluating methylphenidate treatment after TBI have focused only on cognitive function reporting improved cognitive function with faster information processing speed and enhanced working memory and attention span (14–21). A single dose of methylphenidate improved cognitive function and brain functionality compared to placebo in participants suffering from post-TBI symptoms (22,23). Most of these have been short-term studies covering a period between 1 day and 6 weeks and included participants suffering from mild or more severe brain injuries.

This clinical follow-up study was designed to evaluate the long-term effect and safety of methylphenidate treatment. We also evaluated the effect after a four-week treatment break and compared the subjective and objective effects with and without methylphenidate. Patients who had discontinued methylphenidate during this long-term study were also included in this follow-up, as it was our intention to compare the long-term effects on mental fatigue in patients with and without methylphenidate treatment.

Method

Before inclusion in the study (Phase A, Figure 1), the participants were diagnosed with post-concussion syndrome (ICD10 F07.2) having suffered from the consequences of a mild TBI for more than 6 months. They reported subjective complaints of mental fatigue and associated post-concussive symptoms. Age for inclusion was 18–65 years, and having a Glasgow Outcome Scale (extended version – GOS-E), of 5 or higher. The participants were otherwise classified as being healthy and fully rehabilitated physically, with the exception of cognitive impairments and mental fatigue.

The participants were recruited from a series of referrals to the Multidisciplinary Pain Centre at Kungälv Hospital or by the Department of Neurology, Sahlgrenska University Hospital, Gothenburg.

The trial was conducted in compliance with the protocol, good clinical practice (GCP) and the Declaration of Helsinki. The study was approved by The Swedish Central Ethical Review Board and The Swedish Medical Products Agency. All participants gave their written informed consent before inclusion.

Seventeen of 18 patients who had continued with methylphenidate were followed-up in the clinic. Mean time with methylphenidate treatment was 5.5 years (range: between 6 years and 4 months and 4 years and 5 months). All patients who were followed-up at the clinic responded to questionnaires concerning their mental fatigue with the Mental Fatigue Scale (MFS) (24), and depression and anxiety with the Comprehensive Psychopathological Rating Scale (CPRS). These scales have a similar design with a maximal rating of 3. MFS comprised 14 items and the depression and anxiety scales included nine items each. The patients were also assessed for cognitive function measuring information processing speed with the Digit Symbol Coding (DSC) (25); attention with the Trail Making Test (TMT) A and B (26), TMT C and D (27) and working memory with the Digit Span, (DS) (25). For the sake of the patient’s safety, blood pressure, heart rate and ECG readings were taken. One participant did not attend the clinic for the MPH follow-up, despite several reminders, and the reason for this is unknown. In total, 17 patients were followed-up at the clinic.

After a period of discontinued medication with methylphenidate, four patients resumed treatment with methylphenidate (not shown in Table 1). These patients are not included in the clinical follow-up analysis since, they had not followed the original study protocol.

Table 1. Data from start of the study (baseline) and at follow-up after approximately 5.5 years. Mean and standard deviation (in brackets), age at baseline, and employment status given as a percent of full-time employment, mean values as a percent and numbers of individuals at each respective level (100% = 40 h/week).

	MPH baseline	MPH follow-up#	No MPH baseline	No MPH follow-up *	No MPH, not answering, baseline
	n = 17		n = 15		n = 15
Age (years)	46 (9) 10/7		40 (12) 9/10		42 (10) 8/7
Sex females/males
Education	4 elementary 5 high school 8 university		7 high school 8 university		1 elementary 11 high school 3 university
MFS	24 (5)	16 (5)	20 (5)	20(6)	23 (7)
Employment status	28%	28% 9: 0% 1: 25% 5: 50% 0: 75% 2:100%	42%	41% 7: 0% 0: 25% 3: 50% 1: 75% 4: 100%	23%

MPH = methylphenidate, MFS = mental fatigue scale, n = numbers.

The dose of methylphenidate had been individually adjusted to tolerance levels during the first 3 months of the study (Phase A, Figure 1). A slow increase of methylphenidate administration during Phase A facilitated the benefit of individual dosing treatments. The mean dose at 5.5 years follow-up was 58.5 mg/day (range: 40–80 mg/day). Short-acting methylphenidate was used during Phase A (Figure 1). The time interval between intakes of methylphenidate was 4 h. Later, a few patients tried long-acting methylphenidate, but only one preferred long-acting methylphenidate.

The patients who had discontinued methylphenidate were all contacted by mail and were asked to respond to the same questionnaires as those who had attended the clinic. Of these, 19 answered the questionnaires, including the four referred to above who had resumed medication after a break. These patients were reminded once by e-mail. Of these, 15 did not reply. The various reasons why they had discontinued are reported in Figure 1. More detailed information can be found in previous reports (4,10,12,13).

We also sought to study the effect of a four-week treatment break in order to compare subjective and objective effects both with and without methylphenidate after a mean period of 5.5 years. Four-week break was used as methylphenidate has a short half-life of 2.0–3.0 h and a short duration of action (28) and no carry-over effect was expected after 4 weeks and this time frame has previously been found to be acceptable with good compliance (13). The purpose of this was to assess whether methylphenidate still had an effect.

Statistics

A two-way within-subjects ANOVA was used to compare the group with methylphenidate treatment and the group without methylphenidate. Paired t-test was used for comparison of changes over time for a single group and t-test, ANOVA was used for basic group comparison (age and sex) and the chi-square test for categorical data. Bonferroni adjustment was done for multiple comparisons. SPSS 21.0 for Windows was used for data analysis.

Results

The groups with and without methylphenidate had statistically equivalent distributions for age, sex, and education, including the participants not responding to the questionnaire (Table 1). Employment status did not differ between the groups who had been followed-up (Chi-Square p = .508, Table 1).

A two-way within-subjects ANOVA was used to compare the effect over time between the group with methylphenidate and the group without methylphenidate. This revealed significant interactions with large effect sizes for the MFS, CPRS depression and CPRS anxiety scales (Table 2). These interactions are illustrated in Figure 2. A post hoc-paired t-test also showed significant treatment group improvement in MFS, depression, and anxiety (all with p < .001), while no significant change was found for the group who had discontinued methylphenidate treatment, irrespective of reason.

Table 2. Results from the two-way within-subjects ANOVA showing interaction effect and mean and standard deviation at baseline and at follow-up (mean 5.5 years) for the groups with (+) and without (–) methylphenidate.

	Baseline (sd)	5.5 years (sd)	df	F-value	p-Value	η^2
MFS +MPH	24.2 (4.6)	15.6 (4.6)	16.14	20.086	<0.001	0.401
MFS – MPH	19.7 (4.5)	20.1 (6.5)
Depression +MPH	10.6 (3.8)	5.6 (2.7)	16.14	19.788	<0.001	0.397
Depression – MPH	7.6 (3.1)	8.2 (3.2)
Anxiety +MPH	10.6 (4.3)	6.6 (3.3)	16.14	9.316	0.005	0.237
Anxiety – MPH	8.7 (3.9)	8.0 (3.2)

MFS: Mental Fatigue Scale; MPH: methylphenidate; η²:partial eta square (effect size).

Cognition results at follow-up for the methylphenidate group

Compared to baseline, significantly improved processing speed was found after 5.5 years with methylphenidate treatment (Table 3). No significant improvement was found for attention and working memory although the mean values were improved.

Table 3. Cognitive tests. Comparison between baseline data with no methylphenidate and with use of methylphenidate after a mean period of 5.5 years. Mean and standard deviation and statistical comparison with paired t-test.

Test	Df	Baseline	5.5 years	p-value
TMT A	14	40 (18)	30 (11)	0.011
TMT B	14	79 (29)	78 (39)	0.809
TMT C	14	88 (37)	77 (31)	0.058
TMT D	14	143 (75)	122 (63)	0.323
DSC	15	60 (23)	70 (20)	0.008*
DS	15	14 (3)	16 (3)	0.089

TMT: Trail Making Test; DSC: Digit Symbol Coding; DS: Digit Span.

*Statistical difference indicated after correction for multiple comparisons (Bonferroni). Missing data for TMT at baseline for one patient and for all tests for one patient at follow-up.

We found a clear deterioration in mental fatigue, depression, and anxiety ratings as well as slower processing speed when methylphenidate was withdrawn (Table 4). No functional recovery was found as these levels returned to baseline when methylphenidate was withdrawn. Missing data are reported from three patients.

Table 4. A four-week treatment break after 5.5 years of methylphenidate treatment. Effect with and without methylphenidate. Mean (standard deviation), p-value from paired t-test.

	df	With MPH	Without MPH	p-value
MFS	15	15.5 (5)	22.4 (4)	<0.001*
Depression, CPRS	15	5.7 (3)	8.5 (4)	0.004*
Anxiety, CPRS	15	6.5 (3)	8.7 (4)	0.001*
DSC	13	70.0 (21)	60.4 (21)	0.002*

MPH: methylphenidate; MFS: Mental Fatigue Scale; CPRS: Comprehensive Psychopathological Rating Scale; DSC: Digit Symbol Coding.

*Statistical difference indicated after correction for multiple comparisons (Bonferroni).

Methylphenidate was well tolerated during the long treatment period of approximately 5.5 years and the clinical effects remained without any adjustment of dose. Compared to baseline, slight increases in heart rate and blood pressure were found, but these values remained within the normal range (Table 5). Methylphenidate did not induce any electrocardiographic (ECG) changes. No serious adverse effects were reported. No signs of dependence or misuse were reported.

Table 5. Blood pressure and heart rate at baseline and at follow-up (5.5 years). Mean and standard deviation and statistics (paired t-test).

	df	Baseline	5.5 years MPH	p-Value
Heart rate	16	71 (10)	78 (9)	0.061
Systolic BP	16	125 (15)	132 (10)	0.032
Diastolic BP	14	77 (9)	84 (8)	0.019

Discussion

Long-term treatment with methylphenidate for a period of approximately 5.5 years after a mild TBI with lasting post-brain injury symptoms showed the possibility to improve mental fatigue, emotional distress, and cognitive function. The effect was found to be stable and safe over the years. The patients were carefully followed-up in the clinical setting, including drug consumption (every 3–6 months in the long-term perspective). No signs of misuse of methylphenidate were found during this period and no extra tablets were prescribed. Furthermore, withdrawal of methylphenidate worsened the condition, indicating that methylphenidate does not give rise to any long-term basic changes, at least for those who continued in this study and who suffered from chronic post-brain injury symptoms. Thus, the treatment effect of methylphenidate seems to be reversible even after long-term treatment and thus continued treatment with methylphenidate is a prerequisite for long-term improvement. These factors indicate a positive effect of methylphenidate on mental fatigue and cognitive impairments after a mild TBI.

In comparison, the group who discontinued methylphenidate treatment, irrespective of reason, did not report any change in mental fatigue, as well as depression and anxiety at this follow-up. Figure 1 shows that the reason for terminating methylphenidate treatment varied. Five patients ceased treatment on their own initiative, as they no longer felt the need to continue and their rating on MFS was close to cutoff (10.5). Others still suffered from mental fatigue but did not experience any positive effect or could not continue due to medical reasons, showing that methylphenidate is not a treatment option for every-one. However, methylphenidate might be an important component in the toolbox for treatment and rehabilitation of these patients. A further four patients had, after a period of no methylphenidate resumed treatment, but were not included in the above follow-up analysis as they had not followed the study protocol.

Our study demonstrated that there had been no improvements in long-term or chronic mental fatigue and cognitive impairments when methylphenidate was withdrawn. This is in accordance with a scoping review from 45 studies, where approximately half of the individuals with a single mild TBI demonstrated long-term cognitive impairment (29). The authors stated that this contrasts with the prevailing view that symptoms are resolved within 3 months after a mild TBI, and the widely reported 15% incidence of long-term post-concussion symptoms is an underestimate (29). Their reporting of long-term or chronic cognitive symptoms and poorer community participation 4 years after a mild TBI, compared to a matched control group (30) is also in accordance with what we have found in this follow-up study. From this, we can conclude that a careful assessment of long-term mental fatigue and cognitive impairment after a mild TBI is warranted.

Currently, the understanding of underpinning mechanism of pathological mental fatigue after TBI is unknown, and also the effect methylphenidate may have for the results in this study.

A theoretical explanation has been suggested based on neuroinflammation with decreased astroglial clearance of extracellular glutamate, disintegration of the blood–brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, resulting in diminished glutamate transmission (31). Chronic inflammation mainly in subcortical regions with increased microglial activation was present up to 17 years after a TBI (32). In an experimental mouse model of TBI, long-term microglial activation, remote from the initial injury site after a focal TBI was reported, and was suggested to have a major role in prolonged inflammatory processes and be deleterious to the thalamic network (33). Fatigue in neurological disorders has been suggested to be related to circuits that connect basal ganglia, amygdala, the thalamus and frontal cortex (34). Studies of mental fatigue after TBI using functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS) indicate a dysfunction within the cortico-striatal-thalamic circuits (35–40). These circuits mediate motivation, learning, planning, goal-directed behavior and emotion regulation and the integration of networks is important for appropriate behavior and cognitive functioning (41). Cognitive impairment associated with mental fatigue after TBI has been related to reduced processing speed and attention (27,42–48). Methylphenidate inhibits dopamine and norepinephrine transporter resulting in increased concentration in the extra-neuronal space and enhance neurotransmission (49). Chronic down-regulation of norepinephrine receptors associated with decreased signaling and chronic dopaminergic hypofunction are found in experimental TBI models (50). Hypothetically, based on the theoretical summation above, an inefficient and energy-deprived neuronal network could benefit from methylphenidate with enhanced dopamine and norepinephrine signaling resulting in improved cognitive function, and this in turn may alleviate the experience of mental fatigue. However, methylphenidate may not improve the mental energy as the participants in this study were not able to improve their working hours (Table 1).

A principal limitation of the study is the small sample size. Another limitation is that the study was not placebo controlled during Phase A. Future randomized placebo-control studies with a larger number of patients are warranted, but such studies could not be expected to cover such a long treatment period as this study.

Conclusion

We suggest methylphenidate to be a possible treatment option for patients with post-TBI symptoms including mental fatigue and cognitive complaints. Methylphenidate was well tolerated over a longer treatment period and the effect remained without any adjustment of dose. When methylphenidate provides the patient with a positive effect, it enhances the patient’s well-being. However, methylphenidate is not a treatment option for every-one. We recommend that methylphenidate should only be administered to patients in conjunction with a careful monitoring by a doctor who is experienced in caring for patients with traumatic brain injury.

Figure 1. Study flowchart from the start of the study to follow-up after 5.5 years.

Figure 2. The significant interaction effect is described in the figure for mental fatigue (MFS, 14 items), CPRS depression and CPRS anxiety (nine items for both of these two scales). A significant decrease was found for all three scales for the group treated with methylphenidate. +MPH with, and – MPH without methylphenidate.

Acknowledgments

Silva Litrop and Mona Roos are acknowledged for clinical support at Kungälv Hospital.

Additional information

Funding

This work was supported by grants from The Research and Development Centre, Gothenburg and Södra Bohuslän VGFOUGSB-804271.