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Treatment of Acute Mania with Modafinil Monotherapy
CORRESPONDENCE Treatment of Acute Mania with Modafinil Monotherapy To the Editor: n mania, increased catecholaminergic neurotransmission associated with a state of increased arousal is hypothesized. However, hypnotics and neuroleptics may not rapidly improve manic symptoms. Furthermore, in some but not in all manic patients, rapid declines of vigilance levels and intrusion of sleep spindles occur within the first minute of electroencephalography (EEG) under resting conditions with eyes closed (1,2). Based on this observation, one could infer that manic behavior may also reflect an autoregulatory attempt to stabilize vigilance by creating a stimulating environment (3). Such a mechanism could apply to the hyperactive behavior of patients with attention-deficit/hyperactivity disorder (ADHD) (4), which is associated with an unstable regulation of vigilance (5). Accordingly, the seemingly paradoxical therapeutic effects of psychostimulants in ADHD could be explained by their vigilance-stabilizing properties (6). Positive effects of psychostimulants have been observed in children with ADHD and severe mood dysregulation (7). It is important to note that manic episodes triggered by psychostimulants have rarely been reported (8) and a systematic Food and Drug Administration analysis revealed a rather low risk for induction of mania (9). Therefore, stimulants might be an option in the treatment of acute mania. Accordingly, most publications on psychostimulants in mania reported an improvement within 1 or 2 hours of first dose (10 –12). Modafinil is a new substance with vigilance-stabilizing properties that has not shown an increased risk of triggering manic switches in bipolar disorder (13–15). Here we report, to our knowledge for the first time, a case of successful treatment of acute mania with modafinil monotherapy.
I
Results. Mrs. D. is a 49-year-old woman with a 9-year history of bipolar disorder who was referred to the hospital with an acute manic episode. She had been treated for a depressive episode 2 months previously. One month before admission, she had complained about agitation and sleep disturbances. Antidepressant medication with escitalopram was stopped 2 days before admission when the manic syndrome was diagnosed. At time of admission, she had elevated mood with grandiosity, psychomotor agitation, and increased energy and was gesticulating. There was pressure of speech with loosened associa-
tions. Delusions and hallucinations were not present. Severity of mania was rated by three blinded, independent raters on the Young Mania Rating Scale (YMRS) (Figure 1). At admission (day 0), the YMRS score was 21 points. After ruling out contraindications and obtaining informed consent, we proposed treatment with modafinil. On day 1, Mrs. D. received two doses (200 mg each) of modafinil. A rapid decline in manic symptoms was observed (YMRS ⫽ 15) approximately 60 minutes after the initial drug administration. Mrs. D. reported a remarkable tiredness and described the medication as comfortable and calming; these effects lasted 2 hours. A similar effect was noticed by the patient after the second dose. In the next days, modafinil was increased to 800 mg in a stepwise manner, resulting in a further decline of manic symptoms. Already on day 3, she stayed in bed reading a magazine, and on day 4, she slept 8 hours continuously for the first time. On day 5, the manic symptoms were almost fully remitted (YMRS ⫽ 7.5). The medication with modafinil was mostly well tolerated. On day 2, the patient reported presternal sensations before the first medication but the electrocardiogram was unremarkable. On day 5, after a modafinil intake of 400 mg, she reported feeling weak and dizzy. After the following dose of 100 mg, she declined further medication. Modafinil was stopped and a planned longterm treatment with lithium was initiated. Due to poor compliance, lithium plasma levels only increased slowly (day 13: .14 mmol/L, day 22: .29 mmol/L, and day 26: .35 mmol/L).
Electroencephalography. A 10-minute resting EEG with closed eyes was taken before first administration of modafinil, at days 1 and 8. The EEG processing has been reported in greater detail elsewhere (16,17). Briefly, each recording was divided into 1-second segments, which were then subjected to computerbased vigilance stage classification. Six stages ranging from relaxed wakefulness to sleep onset were distinguished: from high-vigilance stages A with dominant alpha activity (subdivided into stages A1, A2, and A3 according to the degree of alphaanteriorization) to low-vigilance stages B (subdivided into stages B1 with dominant low-voltage beta activity and B2/3 with increasing delta and theta activity) and stage C with signs of sleep onset (i.e., sleep spindles or K-complexes).
Figure 1. YMRS scores in a patient during treatment with modafinil. Rating was performed by three blinded raters based on video-recorded interviews done by a physician not involved in the study. Due to titration at the time of the interview, dose taken until YMRS interview and daily dose are given. YMRS, Young Mania Rating Scale.
0006-3223/$36.00
BIOL PSYCHIATRY 2010;67:e55– e57 © 2010 Society of Biological Psychiatry
e56 BIOL PSYCHIATRY 2010;67:e55– e57
Correspondence
Figure 2. Time course of EEG frequency spectra. A 31-channel EEG was recorded at admission (day 0) and after modafinil treatment (day 8). Shown are the averaged time courses from derivations O1-TP9 and O2-TP10. Before modafinil treatment (A) the alpha-activity was discontinuous indicating an unstable vigilance regulation. After modafinil treatment (B), alpha activity was more stable, with the patient remaining mostly in higher vigilance stages. This was paralleled by a clinical improvement of the manic symptoms, as reflected in YMRS score improvements from 21 points on admission to 7 points at day 8. EEG, electroencephalogram; YMRS, Young Mania Rating Scale.
The recording at admission (Figure 2) revealed an unstable vigilance regulation with rapid switches between vigilance stages (A stages: 41.6%; B stages: 46.7%, artefacts: 11.6%). After the first dose of medication (day 1, not shown), the EEG-alpha component remained more stable during the first minute of the recording, but vigilance later dropped to still lower stages. At day 8 (Figure 2), EEG-vigilance analysis showed only rare and short drops to lower vigilance stages (A stages: 76.7%; B stages: 5.8%, artefacts: 17.5%) indicating a stabilization of EEG-vigilance.
psychostimulants. In line with this, in this case, the EEG showed a stabilization during modafinil treatment as reported by others (2,11). Alternative interpretations for the observed improvement of mania comprise spontaneous recovery, improved executive control of mood, or unspecific inpatient treatment. However, our findings also support the concept of manic behavior as an autoregulatory attempt to stabilize vigilance by increased external stimulation (3,4).
Discussion. To our knowledge, this is the first report of the
We thank Dr. Ivonne Burgos Guerrero for conducting the Young Mania Rating Scale interviews. P. Schönknecht has received sponsorship and honoraria for lectures from Lilly, AstraZeneca, Novartis, Pfizer, JanssenCilag, and Merz. U. Hegerl has been or is participating in advisory boards of Lilly, Wyeth, Lundbeck, and Sanofi-Aventis. He received financial support for an Investigator Initiated Trial from Lundbeck. He received honoraria for single lectures as well as sponsoring for symposia and an Internet service
treatment of acute mania with modafinil monotherapy. Blinded ratings revealed a rapid improvement of manic symptoms as indicated by a decline in YMRS score from 21 to 7 points within 5 days. An antimanic effect of modafinil was regularly observed within 1 hour after drug administration. Such rapid effects of psychostimulants have also been reported by other authors (9 –11,18,19). This observation supports the idea that the antimanic effect is due to the vigilance-enhancing properties of www.sobp.org/journal
BIOL PSYCHIATRY 2010;67:e55– e57 e57
Correspondence from Cephalon and other pharmaceutical companies, health insurances, and other parties. The remaining authors report no biomedical financial interests or potential conflicts of interest. Peter Schoenknecht Department of Psychiatry University Hospital Leipzig AöR Semmelweisstrasse 10 04103 Leipzig, Germany E-mail: [email protected] Sebastian Olbrich
5. 6. 7.
8. 9.
Department of Psychiatry University Hospital Leipzig Leipzig, Germany
10.
Christian Sander Department of Psychiatry University Hospital Leipzig Leipzig, Germany
11. 12.
Peter Spindler Department of Psychiatry University Hospital Leipzig Leipzig, Germany
13. 14. 15.
Ulrich Hegerl Department of Psychiatry University Hospital Leipzig Leipzig, Germany
16.
17. 1. Van Sweden B (1986): Disturbed vigilance in mania. Biol Psychiatry 21: 311–313. 2. Small JG, Milstein V, Malloy FW, Medlock CE, Klapper MH (1999): Clinical and quantitative EEG studies of mania. J Affect Disord 53:217–224. 3. Hegerl U, Sander C, Olbrich S, Schönknecht P (2009): Are psychostimulants a treatment option in mania? Pharmacopsychiatry 42:169 –174. 4. Hegerl U, Himmerich H, Engmann B, Hensch T (2010): Mania and attention-deficit/hyperactivity disorder: Common symptomatology, com-
18. 19.
mon pathophysiology and common treatment? Curr Opin Psychiatry 23:1–7. Carskadon MA, Dement WC (1977): Sleep tendency: An objective measure of sleep loss. J Sleep Res 6:200. Pliszka SR (2007): Pharmacologic treatment of attention-deficit/hyperactivity disorder: Efficacy, safety and mechanisms of action. Neuropsychol Rev 17:61–72. Waxmonsky J, Pelham W, Gnagy E, Cummings M, O’Connor B, Majumdar A, et al. (2008): The efficacy and tolerability of methylphenidate and behaviour modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation. J Child Adolesc Psychopharmacol 18:573–588. Vorspan F, Warot D, Consoli A, Cohen D, Mazet P (2005): Mania in a boy treated with modafinil for narcolepsy. Am J Psychiatry 162:813– 814. Ross RG (2006): Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry 163:1149 –1152. Beckmann H, Heinemann H (1976): D-amphetamine in manic syndrome. Drug Res 26:1185–1186. Brown WA, Mueller B (1979): Alleviation of manic symptoms with catecholamine agonists. Am J Psychiatry 136:230 –231. Bschor T, Muller-Oerlinghausen B, Ulrich G (2001): Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: A case study. Clin Electroencephalogr 32:36 –39. Menza MA, Kaufman KR, Castellanos A (2000): Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 61:378 –381. Fernandes PP, Petty F (2003): Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother 37:1807–1809. Frye MA, Grunze H, Suppes T, McElroy SL, Keck PE Jr, Walden J, et al. (2007): A placebo-controlled evaluation of adjunctive Modafinil in the treatment of bipolar depression. Am J Psychiatry 164:1242–1249. Hegerl U, Stein M, Mulert C, Mergl R, Olbrich S, Dichgans E, et al. (2008): EEG-vigilance differences between patients with borderline personality disorder, patients with obsessive-compulsive disorder and healthy controls. Eur Arch Psychiatry Clin Neurosci 258:137–143. Olbrich S, Mulert C, Karch S, Trenner M, Leicht G, Pogarell O, Hegerl U (2009): EEG-vigilance and BOLD effect during simultaneous EEG/fMRI measurement. Neuroimage 45:319 –332. Janowsky DS, Elyousef MK, Davis JM, Sekerke HJ (1973): Provocation of schizophrenic symptoms by intravenous administration of methylphenidate. Arch Gen Psychiatry 28:185–191. Garvey MJ, Hwang S, Teubner-Rhodes D, Zander J, Rhem C (1987): Dextroamphetamine treatment of mania. J Clin Psychiatry 48:412– 413.
doi:10.1016/j.biopsych.2009.12.021
www.sobp.org/journal
I
Results. Mrs. D. is a 49-year-old woman with a 9-year history of bipolar disorder who was referred to the hospital with an acute manic episode. She had been treated for a depressive episode 2 months previously. One month before admission, she had complained about agitation and sleep disturbances. Antidepressant medication with escitalopram was stopped 2 days before admission when the manic syndrome was diagnosed. At time of admission, she had elevated mood with grandiosity, psychomotor agitation, and increased energy and was gesticulating. There was pressure of speech with loosened associa-
tions. Delusions and hallucinations were not present. Severity of mania was rated by three blinded, independent raters on the Young Mania Rating Scale (YMRS) (Figure 1). At admission (day 0), the YMRS score was 21 points. After ruling out contraindications and obtaining informed consent, we proposed treatment with modafinil. On day 1, Mrs. D. received two doses (200 mg each) of modafinil. A rapid decline in manic symptoms was observed (YMRS ⫽ 15) approximately 60 minutes after the initial drug administration. Mrs. D. reported a remarkable tiredness and described the medication as comfortable and calming; these effects lasted 2 hours. A similar effect was noticed by the patient after the second dose. In the next days, modafinil was increased to 800 mg in a stepwise manner, resulting in a further decline of manic symptoms. Already on day 3, she stayed in bed reading a magazine, and on day 4, she slept 8 hours continuously for the first time. On day 5, the manic symptoms were almost fully remitted (YMRS ⫽ 7.5). The medication with modafinil was mostly well tolerated. On day 2, the patient reported presternal sensations before the first medication but the electrocardiogram was unremarkable. On day 5, after a modafinil intake of 400 mg, she reported feeling weak and dizzy. After the following dose of 100 mg, she declined further medication. Modafinil was stopped and a planned longterm treatment with lithium was initiated. Due to poor compliance, lithium plasma levels only increased slowly (day 13: .14 mmol/L, day 22: .29 mmol/L, and day 26: .35 mmol/L).
Electroencephalography. A 10-minute resting EEG with closed eyes was taken before first administration of modafinil, at days 1 and 8. The EEG processing has been reported in greater detail elsewhere (16,17). Briefly, each recording was divided into 1-second segments, which were then subjected to computerbased vigilance stage classification. Six stages ranging from relaxed wakefulness to sleep onset were distinguished: from high-vigilance stages A with dominant alpha activity (subdivided into stages A1, A2, and A3 according to the degree of alphaanteriorization) to low-vigilance stages B (subdivided into stages B1 with dominant low-voltage beta activity and B2/3 with increasing delta and theta activity) and stage C with signs of sleep onset (i.e., sleep spindles or K-complexes).
Figure 1. YMRS scores in a patient during treatment with modafinil. Rating was performed by three blinded raters based on video-recorded interviews done by a physician not involved in the study. Due to titration at the time of the interview, dose taken until YMRS interview and daily dose are given. YMRS, Young Mania Rating Scale.
0006-3223/$36.00
BIOL PSYCHIATRY 2010;67:e55– e57 © 2010 Society of Biological Psychiatry
e56 BIOL PSYCHIATRY 2010;67:e55– e57
Correspondence
Figure 2. Time course of EEG frequency spectra. A 31-channel EEG was recorded at admission (day 0) and after modafinil treatment (day 8). Shown are the averaged time courses from derivations O1-TP9 and O2-TP10. Before modafinil treatment (A) the alpha-activity was discontinuous indicating an unstable vigilance regulation. After modafinil treatment (B), alpha activity was more stable, with the patient remaining mostly in higher vigilance stages. This was paralleled by a clinical improvement of the manic symptoms, as reflected in YMRS score improvements from 21 points on admission to 7 points at day 8. EEG, electroencephalogram; YMRS, Young Mania Rating Scale.
The recording at admission (Figure 2) revealed an unstable vigilance regulation with rapid switches between vigilance stages (A stages: 41.6%; B stages: 46.7%, artefacts: 11.6%). After the first dose of medication (day 1, not shown), the EEG-alpha component remained more stable during the first minute of the recording, but vigilance later dropped to still lower stages. At day 8 (Figure 2), EEG-vigilance analysis showed only rare and short drops to lower vigilance stages (A stages: 76.7%; B stages: 5.8%, artefacts: 17.5%) indicating a stabilization of EEG-vigilance.
psychostimulants. In line with this, in this case, the EEG showed a stabilization during modafinil treatment as reported by others (2,11). Alternative interpretations for the observed improvement of mania comprise spontaneous recovery, improved executive control of mood, or unspecific inpatient treatment. However, our findings also support the concept of manic behavior as an autoregulatory attempt to stabilize vigilance by increased external stimulation (3,4).
Discussion. To our knowledge, this is the first report of the
We thank Dr. Ivonne Burgos Guerrero for conducting the Young Mania Rating Scale interviews. P. Schönknecht has received sponsorship and honoraria for lectures from Lilly, AstraZeneca, Novartis, Pfizer, JanssenCilag, and Merz. U. Hegerl has been or is participating in advisory boards of Lilly, Wyeth, Lundbeck, and Sanofi-Aventis. He received financial support for an Investigator Initiated Trial from Lundbeck. He received honoraria for single lectures as well as sponsoring for symposia and an Internet service
treatment of acute mania with modafinil monotherapy. Blinded ratings revealed a rapid improvement of manic symptoms as indicated by a decline in YMRS score from 21 to 7 points within 5 days. An antimanic effect of modafinil was regularly observed within 1 hour after drug administration. Such rapid effects of psychostimulants have also been reported by other authors (9 –11,18,19). This observation supports the idea that the antimanic effect is due to the vigilance-enhancing properties of www.sobp.org/journal
BIOL PSYCHIATRY 2010;67:e55– e57 e57
Correspondence from Cephalon and other pharmaceutical companies, health insurances, and other parties. The remaining authors report no biomedical financial interests or potential conflicts of interest. Peter Schoenknecht Department of Psychiatry University Hospital Leipzig AöR Semmelweisstrasse 10 04103 Leipzig, Germany E-mail: [email protected] Sebastian Olbrich
5. 6. 7.
8. 9.
Department of Psychiatry University Hospital Leipzig Leipzig, Germany
10.
Christian Sander Department of Psychiatry University Hospital Leipzig Leipzig, Germany
11. 12.
Peter Spindler Department of Psychiatry University Hospital Leipzig Leipzig, Germany
13. 14. 15.
Ulrich Hegerl Department of Psychiatry University Hospital Leipzig Leipzig, Germany
16.
17. 1. Van Sweden B (1986): Disturbed vigilance in mania. Biol Psychiatry 21: 311–313. 2. Small JG, Milstein V, Malloy FW, Medlock CE, Klapper MH (1999): Clinical and quantitative EEG studies of mania. J Affect Disord 53:217–224. 3. Hegerl U, Sander C, Olbrich S, Schönknecht P (2009): Are psychostimulants a treatment option in mania? Pharmacopsychiatry 42:169 –174. 4. Hegerl U, Himmerich H, Engmann B, Hensch T (2010): Mania and attention-deficit/hyperactivity disorder: Common symptomatology, com-
18. 19.
mon pathophysiology and common treatment? Curr Opin Psychiatry 23:1–7. Carskadon MA, Dement WC (1977): Sleep tendency: An objective measure of sleep loss. J Sleep Res 6:200. Pliszka SR (2007): Pharmacologic treatment of attention-deficit/hyperactivity disorder: Efficacy, safety and mechanisms of action. Neuropsychol Rev 17:61–72. Waxmonsky J, Pelham W, Gnagy E, Cummings M, O’Connor B, Majumdar A, et al. (2008): The efficacy and tolerability of methylphenidate and behaviour modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation. J Child Adolesc Psychopharmacol 18:573–588. Vorspan F, Warot D, Consoli A, Cohen D, Mazet P (2005): Mania in a boy treated with modafinil for narcolepsy. Am J Psychiatry 162:813– 814. Ross RG (2006): Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry 163:1149 –1152. Beckmann H, Heinemann H (1976): D-amphetamine in manic syndrome. Drug Res 26:1185–1186. Brown WA, Mueller B (1979): Alleviation of manic symptoms with catecholamine agonists. Am J Psychiatry 136:230 –231. Bschor T, Muller-Oerlinghausen B, Ulrich G (2001): Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: A case study. Clin Electroencephalogr 32:36 –39. Menza MA, Kaufman KR, Castellanos A (2000): Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 61:378 –381. Fernandes PP, Petty F (2003): Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother 37:1807–1809. Frye MA, Grunze H, Suppes T, McElroy SL, Keck PE Jr, Walden J, et al. (2007): A placebo-controlled evaluation of adjunctive Modafinil in the treatment of bipolar depression. Am J Psychiatry 164:1242–1249. Hegerl U, Stein M, Mulert C, Mergl R, Olbrich S, Dichgans E, et al. (2008): EEG-vigilance differences between patients with borderline personality disorder, patients with obsessive-compulsive disorder and healthy controls. Eur Arch Psychiatry Clin Neurosci 258:137–143. Olbrich S, Mulert C, Karch S, Trenner M, Leicht G, Pogarell O, Hegerl U (2009): EEG-vigilance and BOLD effect during simultaneous EEG/fMRI measurement. Neuroimage 45:319 –332. Janowsky DS, Elyousef MK, Davis JM, Sekerke HJ (1973): Provocation of schizophrenic symptoms by intravenous administration of methylphenidate. Arch Gen Psychiatry 28:185–191. Garvey MJ, Hwang S, Teubner-Rhodes D, Zander J, Rhem C (1987): Dextroamphetamine treatment of mania. J Clin Psychiatry 48:412– 413.
doi:10.1016/j.biopsych.2009.12.021
www.sobp.org/journal