- Email: [email protected]
A possible effect of methylphenidate on state anxiety: A single dose, placebo controlled, crossover study in a control group
Psychiatry Research 241 (2016) 232–235
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
A possible effect of methylphenidate on state anxiety: A single dose, placebo controlled, crossover study in a control group Aviv Segev a,b,n, Hila Zahava Gvirts a,b, Kevin Strouse c, Naama Mayseless d, Hagar Gelbard d, Yael Doreen Lewis a, Yael Barnea e, Kfir Feffer a, Simone G. Shamay-Tsoory d, Yuval Bloch a,b a
Shalvata Mental Health Center, Hod Hasharon, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Psychiatry and Behavioral Sciences, Johns Hopkins Hospital, MD, USA d Department of Psychology, University of Haifa, Haifa, Israel e Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel b
art ic l e i nf o
a b s t r a c t
Article history: Received 22 November 2015 Accepted 5 May 2016 Available online 11 May 2016
Methylphenidate affects state-anxiety in ADHD patients. The current study examines the effect of Methylphenidate on state-anxiety in healthy subjects. In a cross-over, randomized, controlled, double-blind study, 36 healthy subjects received either Methylphenidate or placebo. As a group, no change in stateanxiety was detected with Methylphenidate. However, participants reporting higher anxiety levels experienced a significant and specific state-anxiety reduction following Methylphenidate. Moreover, a strong negative correlation was found between the initial-level of anxiety and net-change in state-anxiety. These changes were unrelated to self-perceived attention levels. Our results point to the statedependent effects of Methylphenidate on anxiety. & 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Attention ADHD Cognitive enhancer
1. Introduction Methylphenidate (MPH) is a widely used medication for attention deficit/hyperactivity Disorder (ADHD). Though ethically controversial, it is also used for cognitive-enhancement in healthy populations (McCabe et al., 2005; Outram, 2010). This type of use raised the need to study the efficacy of such a therapy. To date, studies and public attention focused on the different cognitive functions and the increment of improvement achieved by MPH and stimulants (Caviola and Faber, 2015). Since a common use of MPH as a “cognitive-enhancer” is aimed at anxiety-saturated conditions (e.g. exams), it seems that the effects of MPH on anxiety in controls should be evaluated (Liakoni et al., 2015). Anxiety, like attention, is attributed at least partially to catecholamines, and the interplay between them is extremely convergent. MPH is related, at times, to aggravating anxiety (Epstein et al., 2014). This was especially stressed in studies with animal models of ADHD (Vendruscolo et al., 2008). Conversely, a recent meta-analysis of clinical studies using MPH points to the opposite effect, in which MPH reduces anxiety in ADHD patients (Coughlin et al., 2015). In a previous study, our group had shown that stateanxiety reduction following the administration of MPH was n Corresponding author at: Shalvata Mental Health Center, POB 94, Hod Hasharon, Israel. E-mail addresses: [email protected], [email protected] (A. Segev).
http://dx.doi.org/10.1016/j.psychres.2016.05.009 0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
specific to ADHD patients, and was not observed in controls. Although the MPH effect on continuous performance test execution was more pronounced in ADHD patients, controls improved as well. However, the effect on anxiety was discriminative and was observed only in ADHD subjects. In that study, ADHD patients were more anxious than controls, and there was no blind use of a placebo (Bloch et al., 2013). With the rising use of MPH as a cognitive enhancer, studying the effect of MPH on anxiety in healthy subjects can contribute to the understanding of its use in this population and in better typifying its effect on ADHD patients.
2. Methods 2.1. Participants All subjects were recruited through advertisements within the University and in the community. Inclusion criteria were age 21–40, right handed, Hebrew as mother-tongue and a high-school diploma. Exclusion criteria were (a) any neurological or psychiatric illness; (b) any medical conditions contra-indicated when receiving MPH; (c) any learning disability; (d) drug or alcohol abuse; (e) score 60 or higher on the Connor's Adult ADHD Rating Scale.
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
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-7 Baseline
Change in 2nd assessment
Change in 3rd assessment
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Hi Anx, MPH
Low Anx, MPH
Hi Anx, MPH
Low Anx, MPH
Hi Anx, Placebo
Low Anx, Placebo
Hi Anx, Placebo
Low Anx, Placebo
Fig. 1. Net changes in state anxiety, as groups are defined in graph (a) according to initial levels of state-anxiety; and in graph (b) according to trait-anxiety. ANX – anxiety, MPH – methylphenidate.
2.2. Tools Several assessment tools were used: 1) The Spielberger State-Trait-anxiety Inventory (STAI), a measure of both transient (state) and enduring levels (trait) of anxiety; 2) Conners' Adult ADHD Rating Scales (CAARS) (Conners et al., 1999), which measures ADHD symptoms; 3) on a Visual Analog Scale (VAS) (Revill et al., 1976) subjects reported how attentive they were feeling at present; 4) the Structured Clinical Interview for DSM-IV (SCID) - a diagnostic tool for mental disorders, used as a screen tool to verify suitability for the study.
first state-anxiety assessment or level of trait-anxiety. The cutoff defining low vs. high anxiety was a STAI score of 30 – halfway between the minimal score (20) and clinical cutoff (40). Baseline level of anxiety was correlated to the net change in state-anxiety levels during the session using a Pearson test, in order to enable a dimensional perspective. A similar method was performed in order to examine a possible confounding role of gender, order effect and MPH effect on attention level.
3. Results 2.3. Study design 3.1. General This was a randomized, double-blind placebo-controlled, random block order crossover trial. Eligible individuals were scheduled for two assessment visits 2 weeks apart which began at the same time of day. The study was approved by the local IRB. All participants went through an informed consent procedure and then underwent a physical screening (including a medical history interview performed by a physician, a physical examination and an ECG test) as well as a psychiatric screening (based on the SCID semi-structured interview conducted by a psychiatrist and the CAARS for further reassurance of ruling out ADHD). In both sessions, subjects completed VAS and full STAI prior to any intervention. They were randomly assigned to receive MPH 20 mg immediate-release or inert ingredients (placebo). Forty-five minutes after drug administration (during which the participants filled out several questionnaires required for the study), subjects completed VAS and STAI-State questionnaire again and then performed several tasks related to creativity (described elsewhere, unrelated to anxiety and attention). 1.5 h later subjects completed a VAS and STAI-State for a third time. In the second session, medication (MPH/placebo) was crossed-over. 2.4. Statistical analysis We have applied a repeated measure analysis of variance using state-anxiety levels and drug administered as within-subject factors. In order to examine the differential effect of MPH based upon baseline levels of anxiety, we have used a group variable – low vs. high anxiety level, as a between-subject factor. Determination of a baseline level of anxiety could rely on two measures: either by
The 36 Participants were mostly single (92.6%), full-time students (69.0%), young (M ¼25.36 years, SD ¼3.88; range¼ 21–39) and gender balanced (50% males). None of them was a regular user of stimulants. Subjects’ weight range was 47–87 kg. Mean CAARS score was 46.7 (SD 7.3, range 32–58), and mean STAI-Trait was 28.0 (SD 6.4, range 20–49). 3.2. Examining the effect of MPH on state-anxiety A repeated measure analysis of variance with drug (Placebo, MPH) and time (STAI-state assessments 1, 2 & 3) found non-significant interaction (F(2,34) ¼ 0.261, p 40.1). Levels of state-anxiety in the MPH session were 27.06, 26.31 and 27.06, respectively; and 25.42, 25.31 and 26.31 in the placebo session. Follow-up independent t-tests for each assessment point yielded non-significant difference at any time. 3.3. Examining the effect of MPH on state-anxiety in low vs. high anxiety subgroups This was measured by either initial-state or trait-anxiety score. Correlation between those measures was moderate (r ¼0.43. po 0.01), reflecting that although linked, there is a discrepancy between anxiety as a long-lasting characteristic (trait) to the transient situational anxiety exhibited in the morning of the first session (state). Two repeated measure analyses were performed: one with drug and time (as explained), using a between-subject factor of state-anxiety group (low vs. high initial state-anxiety); and a
234
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
second using trait-anxiety group (low vs. high trait-anxiety) as between-subject factor. Both yielded significant interactions (F (2,68) ¼10.4, po 0.001 and F(2,68) ¼ 3.854, p ¼0.026, respectively). Post-hoc analysis using a paired t-test revealed a significant decrease in state-anxiety under the influence of MPH in the highanxiety group for both analyses, initial-state and trait-anxiety (from 37.00 to 31.10, p¼ 0.003 and from 33.00 to 29.00, p ¼0.049, respectively), while on the low-anxiety groups a trend increase was revealed only in initial-state groups and not in trait (from 23.46 to 24.46, p ¼0.073 and from 24.44 to 25.12, p4 0.1, respectively). When comparing the net change in the level of state-anxiety in the high vs. low initial-state-anxiety under the influence of MPH (Fig. 1a), a significant change is detected ( 5.9 vs. 1.23, respectively, p¼ 0.001). When repeating the analysis in the high vs. low trait-anxiety under the influence of MPH (Fig. 1b), similar results reveals ( 4.0 vs. 0.68, respectively, p ¼ 0.03). In both analyses, no significant changes were detected in the placebo sessions. When examining the dimensional effect, a Pearson's correlation between the net change in state-anxiety compared to initial state-anxiety or trait-anxiety under the influence of MPH, reveals a significant strong negative correlation (r¼ 0.638, p o0.001 and r¼ 0.4, p ¼0.016, respectively). 3.4. Examining possible confounding effects (gender, order and attention) To examine a possible gender effect, similar repeated measure analysis was performed, adding gender as the between-subject factor. Non-significant interaction was found (F(2,33) ¼0.351, p 40.1). However, in every assessment point in both sessions, females exhibited a significant or borderline increased state-anxiety (MPH assessments: p ¼0.059, p¼ 0.07 and p ¼0.027; placebo: p ¼0.018, p ¼0.04 and p ¼0.005). To study whether order effects may confound the results, additional repeated measures were performed using the active session (first, last) as a between-subject factor. No interaction was found (F(2,33) ¼1.895, p 40.1). To examine whether the effect of MPH upon anxiety was linked to an effect on perception of attention (measured by VAS), we carried out 2 analyses: a repeated measure analysis of variance with drug and time (VAS-attention at the 3 assessments) as within-subject factors and trait-anxiety group (low vs. high traitanxiety) as between-subject factor. No interaction was found (F (1,34)¼0.607, p 40.1). An additional repeated measure analysis was carried out with drug and time (STAI-state) as within-subject factors and group (low vs. high CAARS score) as between-subject factor. Again, no interaction was found (F(2,68) ¼5.42, p 40.1).
4. Discussion The effect of a single dose of MPH on state-anxiety was dependent on the baseline anxiety of the subject: subjects in the higher range of “normal” anxiety experienced a reduction in stateanxiety, while those in the lower range of “normal” anxiety experienced the opposite effect, though milder. Dimensional approach further substantiates this relation, correlating the initial anxiety to the effect size of MPH. These effects were independent from subjective reports about improvement in attention. In current diagnostic and psychopharmacological thinking, the categorical perspective prevails: we tend to separate the main effect of a treatment (e.g. attention in ADHD) as other effects might be considered non-specific or side effects (e.g. anxiety). Along with modern dimensional approaches, studying effects of MPH on anxiety in a control group enables us to study the less
obvious dimension of the effects of MPH, less burdened by the “shadowing” effect on attention in ADHD patients. Anxiety was repeatedly reported as a side effect of MPH (Lee et al., 2011) and is mentioned as a possible side effect in MPH monographs. However, several studies have reported decreased anxiety followed by administration of MPH (Ahmann et al., 1993). Our study might offer a possible explanation for that paradox: increased anxiety can be a side effect in low-anxiety populations, but for those with anxious features, anxiety will subside. Our results support the understanding that the effects of MPH are not related to a single dimension (attention/cognition); studying the effects on other relevant dimensions (i.e. anxiety) probably contributes to the understanding of both side-effects and therapeutic potentials. While this study focuses on healthy, non-ADHD population, its results suggest that it is important to examine the effects of stateanxiety reduction as a component of the effectiveness of MPH given to ADHD patients. In a previous study, it was suggested that MPH effect on state-anxiety is discriminative to ADHD patients (Bloch et al., 2013). However, integrating the results of the current study, it seems that a multi-dimensional approach, consisting both attention difficulties and anxiety tonus, will better delineate the therapeutic effect of MPH and might contribute to more accurate clinical decision making. Further studies should examine this issue in a research combining ADHD and healthy subjects. The use of MPH and similar stimulants as cognitive-enhancers, though controversial, is gaining popularity (Caviola and Faber, 2015; Liakoni et al., 2015). If verified by additional, larger studies, our results suggest that a possible route of the cognitive-enhancement effect is mediated by state-anxiety reduction. Several studies suggest possible negative cognitive effects of stimulants on healthy individuals (Lakhan and Kirchgessner, 2012), thus emphasizing the need to identify populations that can benefit from MPH as a cognitive-enhancer and decrease possibility of harm. The current study suggests that high anxiety tonus is a possible feature marking healthy individuals that can benefit from MPH. There are several limitations to the current study. The study includes a small, homogenous sample, so replication should be done in order to verify and generalize the results. The design of our study included only a single MPH dose, and therefore cannot attest to the impact of prolonged use of MPH. Attention was only subjectively evaluated; while not insignificant, it should be noted that the sample was comprised of non-ADHD subjects, in which the use of MPH as “cognitive enhancer” is currently driven only by subjective feelings of users, rather than methodical assessments (e.g. continuous performance tests). The latter limitation is also enhanced due to the lack of biological correlates to stress (e.g. physiological adrenergic measures) to demonstrate the effects in objective scales.
Funding This study was supported by the Israeli Scientific Foundation (ISF), grant number 1194/13; the ISF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflicts of interest None of the authors have conflicts of interest to disclose.
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
Acknowledgements The authors wish to express their gratitude to Prof. Rachel Tomer for her guidance and assistance. In addition, the authors thank the Israeli Scientific Foundation (ISF) grant number 1194/13 for its support.
References Ahmann, P.A., Waltonen, S.J., Olson, K.A., Theye, F.W., Van Erem, A.J., LaPlant, R.J., 1993. Placebo-controlled evaluation of Ritalin side effects. Pediatrics 91 (6), 1101–1106. Bloch, Y., Aviram, S., Segev, A., Nitzan, U., Levkovitz, Y., Braw, Y., Mimouni Bloch, A., 2013. Methylphenidate reduces state anxiety during a continuous performance test that distinguishes Adult ADHD patients from controls. J. Atten. Disord. Caviola, L., Faber, N.S., 2015. Pills or push-ups? Effectiveness and public perception of pharmacological and non-pharmacological cognitive enhancement. Front. Psychol. 6, 1852. Conners, C.K., Erhardt, D., Epstein, J.N., Parker, J.D.A., Sitarenios, G., Sparrow, E., 1999. Self-ratings of ADHD symptoms in adults I: Factor structure and normative data. J. Atten. Disord. 3 (3), 141–151. Coughlin, C.G., Cohen, S.C., Mulqueen, J.M., Ferracioli-Oda, E., Stuckelman, Z.D., Bloch, M.H., 2015. Meta-analysis: reduced risk of anxiety with psychostimulant
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treatment in children with attention-deficit/hyperactivity disorder. J. Child Adolesc. Psychopharmacol. 25 (8), 611–617. Epstein, T., Patsopoulos, N.A., Weiser, M., 2014. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst. Rev. 9, CD005041. Lakhan, S.E., Kirchgessner, A., 2012. Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain Behav. 2 (5), 661–677. Lee, J., Grizenko, N., Bhat, V., Sengupta, S., Polotskaia, A., Joober, R., 2011. Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD. BMC Psychiatry 11, 70. Liakoni, E., Schaub, M.P., Maier, L.J., Glauser, G.V., Liechti, M.E., 2015. The use of prescription drugs, recreational drugs, and “soft enhancers” for cognitive enhancement among Swiss secondary school students. PLoS One 10 (10), e0141289. McCabe, S.E., Knight, J.R., Teter, C.J., Wechsler, H., 2005. Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction 100 (1), 96–106. Outram, S.M., 2010. The use of methylphenidate among students: the future of enhancement? J. Med. Ethics 36 (4), 198–202. Revill, S.I., Robinson, J.O., Rosen, M., Hogg, M.I.J., 1976. The reliability of a linear analogue for evaluating pain. Anaesthesia 31 (9), 1191–1198. Vendruscolo, L.F., Izidio, G.S., Takahashi, R.N., Ramos, A., 2008. Chronic methylphenidate treatment during adolescence increases anxiety-related behaviors and ethanol drinking in adult spontaneously hypertensive rats. Behav. Pharm. 19 (1), 21–27.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
A possible effect of methylphenidate on state anxiety: A single dose, placebo controlled, crossover study in a control group Aviv Segev a,b,n, Hila Zahava Gvirts a,b, Kevin Strouse c, Naama Mayseless d, Hagar Gelbard d, Yael Doreen Lewis a, Yael Barnea e, Kfir Feffer a, Simone G. Shamay-Tsoory d, Yuval Bloch a,b a
Shalvata Mental Health Center, Hod Hasharon, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Psychiatry and Behavioral Sciences, Johns Hopkins Hospital, MD, USA d Department of Psychology, University of Haifa, Haifa, Israel e Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel b
art ic l e i nf o
a b s t r a c t
Article history: Received 22 November 2015 Accepted 5 May 2016 Available online 11 May 2016
Methylphenidate affects state-anxiety in ADHD patients. The current study examines the effect of Methylphenidate on state-anxiety in healthy subjects. In a cross-over, randomized, controlled, double-blind study, 36 healthy subjects received either Methylphenidate or placebo. As a group, no change in stateanxiety was detected with Methylphenidate. However, participants reporting higher anxiety levels experienced a significant and specific state-anxiety reduction following Methylphenidate. Moreover, a strong negative correlation was found between the initial-level of anxiety and net-change in state-anxiety. These changes were unrelated to self-perceived attention levels. Our results point to the statedependent effects of Methylphenidate on anxiety. & 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Attention ADHD Cognitive enhancer
1. Introduction Methylphenidate (MPH) is a widely used medication for attention deficit/hyperactivity Disorder (ADHD). Though ethically controversial, it is also used for cognitive-enhancement in healthy populations (McCabe et al., 2005; Outram, 2010). This type of use raised the need to study the efficacy of such a therapy. To date, studies and public attention focused on the different cognitive functions and the increment of improvement achieved by MPH and stimulants (Caviola and Faber, 2015). Since a common use of MPH as a “cognitive-enhancer” is aimed at anxiety-saturated conditions (e.g. exams), it seems that the effects of MPH on anxiety in controls should be evaluated (Liakoni et al., 2015). Anxiety, like attention, is attributed at least partially to catecholamines, and the interplay between them is extremely convergent. MPH is related, at times, to aggravating anxiety (Epstein et al., 2014). This was especially stressed in studies with animal models of ADHD (Vendruscolo et al., 2008). Conversely, a recent meta-analysis of clinical studies using MPH points to the opposite effect, in which MPH reduces anxiety in ADHD patients (Coughlin et al., 2015). In a previous study, our group had shown that stateanxiety reduction following the administration of MPH was n Corresponding author at: Shalvata Mental Health Center, POB 94, Hod Hasharon, Israel. E-mail addresses: [email protected], [email protected] (A. Segev).
http://dx.doi.org/10.1016/j.psychres.2016.05.009 0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
specific to ADHD patients, and was not observed in controls. Although the MPH effect on continuous performance test execution was more pronounced in ADHD patients, controls improved as well. However, the effect on anxiety was discriminative and was observed only in ADHD subjects. In that study, ADHD patients were more anxious than controls, and there was no blind use of a placebo (Bloch et al., 2013). With the rising use of MPH as a cognitive enhancer, studying the effect of MPH on anxiety in healthy subjects can contribute to the understanding of its use in this population and in better typifying its effect on ADHD patients.
2. Methods 2.1. Participants All subjects were recruited through advertisements within the University and in the community. Inclusion criteria were age 21–40, right handed, Hebrew as mother-tongue and a high-school diploma. Exclusion criteria were (a) any neurological or psychiatric illness; (b) any medical conditions contra-indicated when receiving MPH; (c) any learning disability; (d) drug or alcohol abuse; (e) score 60 or higher on the Connor's Adult ADHD Rating Scale.
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
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-7 Baseline
Change in 2nd assessment
Change in 3rd assessment
Baseline
Change in 2nd assessment
Change in 3rd assessment
Hi Anx, MPH
Low Anx, MPH
Hi Anx, MPH
Low Anx, MPH
Hi Anx, Placebo
Low Anx, Placebo
Hi Anx, Placebo
Low Anx, Placebo
Fig. 1. Net changes in state anxiety, as groups are defined in graph (a) according to initial levels of state-anxiety; and in graph (b) according to trait-anxiety. ANX – anxiety, MPH – methylphenidate.
2.2. Tools Several assessment tools were used: 1) The Spielberger State-Trait-anxiety Inventory (STAI), a measure of both transient (state) and enduring levels (trait) of anxiety; 2) Conners' Adult ADHD Rating Scales (CAARS) (Conners et al., 1999), which measures ADHD symptoms; 3) on a Visual Analog Scale (VAS) (Revill et al., 1976) subjects reported how attentive they were feeling at present; 4) the Structured Clinical Interview for DSM-IV (SCID) - a diagnostic tool for mental disorders, used as a screen tool to verify suitability for the study.
first state-anxiety assessment or level of trait-anxiety. The cutoff defining low vs. high anxiety was a STAI score of 30 – halfway between the minimal score (20) and clinical cutoff (40). Baseline level of anxiety was correlated to the net change in state-anxiety levels during the session using a Pearson test, in order to enable a dimensional perspective. A similar method was performed in order to examine a possible confounding role of gender, order effect and MPH effect on attention level.
3. Results 2.3. Study design 3.1. General This was a randomized, double-blind placebo-controlled, random block order crossover trial. Eligible individuals were scheduled for two assessment visits 2 weeks apart which began at the same time of day. The study was approved by the local IRB. All participants went through an informed consent procedure and then underwent a physical screening (including a medical history interview performed by a physician, a physical examination and an ECG test) as well as a psychiatric screening (based on the SCID semi-structured interview conducted by a psychiatrist and the CAARS for further reassurance of ruling out ADHD). In both sessions, subjects completed VAS and full STAI prior to any intervention. They were randomly assigned to receive MPH 20 mg immediate-release or inert ingredients (placebo). Forty-five minutes after drug administration (during which the participants filled out several questionnaires required for the study), subjects completed VAS and STAI-State questionnaire again and then performed several tasks related to creativity (described elsewhere, unrelated to anxiety and attention). 1.5 h later subjects completed a VAS and STAI-State for a third time. In the second session, medication (MPH/placebo) was crossed-over. 2.4. Statistical analysis We have applied a repeated measure analysis of variance using state-anxiety levels and drug administered as within-subject factors. In order to examine the differential effect of MPH based upon baseline levels of anxiety, we have used a group variable – low vs. high anxiety level, as a between-subject factor. Determination of a baseline level of anxiety could rely on two measures: either by
The 36 Participants were mostly single (92.6%), full-time students (69.0%), young (M ¼25.36 years, SD ¼3.88; range¼ 21–39) and gender balanced (50% males). None of them was a regular user of stimulants. Subjects’ weight range was 47–87 kg. Mean CAARS score was 46.7 (SD 7.3, range 32–58), and mean STAI-Trait was 28.0 (SD 6.4, range 20–49). 3.2. Examining the effect of MPH on state-anxiety A repeated measure analysis of variance with drug (Placebo, MPH) and time (STAI-state assessments 1, 2 & 3) found non-significant interaction (F(2,34) ¼ 0.261, p 40.1). Levels of state-anxiety in the MPH session were 27.06, 26.31 and 27.06, respectively; and 25.42, 25.31 and 26.31 in the placebo session. Follow-up independent t-tests for each assessment point yielded non-significant difference at any time. 3.3. Examining the effect of MPH on state-anxiety in low vs. high anxiety subgroups This was measured by either initial-state or trait-anxiety score. Correlation between those measures was moderate (r ¼0.43. po 0.01), reflecting that although linked, there is a discrepancy between anxiety as a long-lasting characteristic (trait) to the transient situational anxiety exhibited in the morning of the first session (state). Two repeated measure analyses were performed: one with drug and time (as explained), using a between-subject factor of state-anxiety group (low vs. high initial state-anxiety); and a
234
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
second using trait-anxiety group (low vs. high trait-anxiety) as between-subject factor. Both yielded significant interactions (F (2,68) ¼10.4, po 0.001 and F(2,68) ¼ 3.854, p ¼0.026, respectively). Post-hoc analysis using a paired t-test revealed a significant decrease in state-anxiety under the influence of MPH in the highanxiety group for both analyses, initial-state and trait-anxiety (from 37.00 to 31.10, p¼ 0.003 and from 33.00 to 29.00, p ¼0.049, respectively), while on the low-anxiety groups a trend increase was revealed only in initial-state groups and not in trait (from 23.46 to 24.46, p ¼0.073 and from 24.44 to 25.12, p4 0.1, respectively). When comparing the net change in the level of state-anxiety in the high vs. low initial-state-anxiety under the influence of MPH (Fig. 1a), a significant change is detected ( 5.9 vs. 1.23, respectively, p¼ 0.001). When repeating the analysis in the high vs. low trait-anxiety under the influence of MPH (Fig. 1b), similar results reveals ( 4.0 vs. 0.68, respectively, p ¼ 0.03). In both analyses, no significant changes were detected in the placebo sessions. When examining the dimensional effect, a Pearson's correlation between the net change in state-anxiety compared to initial state-anxiety or trait-anxiety under the influence of MPH, reveals a significant strong negative correlation (r¼ 0.638, p o0.001 and r¼ 0.4, p ¼0.016, respectively). 3.4. Examining possible confounding effects (gender, order and attention) To examine a possible gender effect, similar repeated measure analysis was performed, adding gender as the between-subject factor. Non-significant interaction was found (F(2,33) ¼0.351, p 40.1). However, in every assessment point in both sessions, females exhibited a significant or borderline increased state-anxiety (MPH assessments: p ¼0.059, p¼ 0.07 and p ¼0.027; placebo: p ¼0.018, p ¼0.04 and p ¼0.005). To study whether order effects may confound the results, additional repeated measures were performed using the active session (first, last) as a between-subject factor. No interaction was found (F(2,33) ¼1.895, p 40.1). To examine whether the effect of MPH upon anxiety was linked to an effect on perception of attention (measured by VAS), we carried out 2 analyses: a repeated measure analysis of variance with drug and time (VAS-attention at the 3 assessments) as within-subject factors and trait-anxiety group (low vs. high traitanxiety) as between-subject factor. No interaction was found (F (1,34)¼0.607, p 40.1). An additional repeated measure analysis was carried out with drug and time (STAI-state) as within-subject factors and group (low vs. high CAARS score) as between-subject factor. Again, no interaction was found (F(2,68) ¼5.42, p 40.1).
4. Discussion The effect of a single dose of MPH on state-anxiety was dependent on the baseline anxiety of the subject: subjects in the higher range of “normal” anxiety experienced a reduction in stateanxiety, while those in the lower range of “normal” anxiety experienced the opposite effect, though milder. Dimensional approach further substantiates this relation, correlating the initial anxiety to the effect size of MPH. These effects were independent from subjective reports about improvement in attention. In current diagnostic and psychopharmacological thinking, the categorical perspective prevails: we tend to separate the main effect of a treatment (e.g. attention in ADHD) as other effects might be considered non-specific or side effects (e.g. anxiety). Along with modern dimensional approaches, studying effects of MPH on anxiety in a control group enables us to study the less
obvious dimension of the effects of MPH, less burdened by the “shadowing” effect on attention in ADHD patients. Anxiety was repeatedly reported as a side effect of MPH (Lee et al., 2011) and is mentioned as a possible side effect in MPH monographs. However, several studies have reported decreased anxiety followed by administration of MPH (Ahmann et al., 1993). Our study might offer a possible explanation for that paradox: increased anxiety can be a side effect in low-anxiety populations, but for those with anxious features, anxiety will subside. Our results support the understanding that the effects of MPH are not related to a single dimension (attention/cognition); studying the effects on other relevant dimensions (i.e. anxiety) probably contributes to the understanding of both side-effects and therapeutic potentials. While this study focuses on healthy, non-ADHD population, its results suggest that it is important to examine the effects of stateanxiety reduction as a component of the effectiveness of MPH given to ADHD patients. In a previous study, it was suggested that MPH effect on state-anxiety is discriminative to ADHD patients (Bloch et al., 2013). However, integrating the results of the current study, it seems that a multi-dimensional approach, consisting both attention difficulties and anxiety tonus, will better delineate the therapeutic effect of MPH and might contribute to more accurate clinical decision making. Further studies should examine this issue in a research combining ADHD and healthy subjects. The use of MPH and similar stimulants as cognitive-enhancers, though controversial, is gaining popularity (Caviola and Faber, 2015; Liakoni et al., 2015). If verified by additional, larger studies, our results suggest that a possible route of the cognitive-enhancement effect is mediated by state-anxiety reduction. Several studies suggest possible negative cognitive effects of stimulants on healthy individuals (Lakhan and Kirchgessner, 2012), thus emphasizing the need to identify populations that can benefit from MPH as a cognitive-enhancer and decrease possibility of harm. The current study suggests that high anxiety tonus is a possible feature marking healthy individuals that can benefit from MPH. There are several limitations to the current study. The study includes a small, homogenous sample, so replication should be done in order to verify and generalize the results. The design of our study included only a single MPH dose, and therefore cannot attest to the impact of prolonged use of MPH. Attention was only subjectively evaluated; while not insignificant, it should be noted that the sample was comprised of non-ADHD subjects, in which the use of MPH as “cognitive enhancer” is currently driven only by subjective feelings of users, rather than methodical assessments (e.g. continuous performance tests). The latter limitation is also enhanced due to the lack of biological correlates to stress (e.g. physiological adrenergic measures) to demonstrate the effects in objective scales.
Funding This study was supported by the Israeli Scientific Foundation (ISF), grant number 1194/13; the ISF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflicts of interest None of the authors have conflicts of interest to disclose.
A. Segev et al. / Psychiatry Research 241 (2016) 232–235
Acknowledgements The authors wish to express their gratitude to Prof. Rachel Tomer for her guidance and assistance. In addition, the authors thank the Israeli Scientific Foundation (ISF) grant number 1194/13 for its support.
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