Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
Letters to the Editors 6. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(5): 561–566. 7. Levitan MG, Papelbaum M, Nardi AE. A review of preliminary observations on agomelatine in the treatment of anxiety disorders. Exp Clin Psychopharmacol. 2012;20(6):504–509. 8. Kasper S, Hamon M. Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant with an innovative mechanism of action. World J Biol Psychiatry. 2009;10(2):117–126. 9. Fornaro M. Agomelatine in the treatment of panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):286–287. 10. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P) New York: Biometrics Research, New York State Psychiatric Institute; 2002. 11. Furukawa TA, Katherine Shear M, Barlow DH, et al. Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. Depress Anxiety. 2009;26(10):922–929. 12. Shear MK, Brown TA, Barlow DH, et al. Multicenter collaborative panic disorder severity scale. Am J Psychiatry. 1997;154:1571–1575. 13. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. 14. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory—II. San Antonio, TX: Psychological Corporation; 1996. 15. Beck AT, Steer RA. Beck Anxiety Inventory Manual. San Antonio, TX: Psychological Corporation; 1993. 16. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483. 17. Leon AC, Shear MK, Portera L, et al. Assessing impairment in patients with panic disorder: the Sheehan Disability Scale. Soc Psychiatry Psychiatr Epidemiol. 1992; 27(2):78–82. 18. Fawcett S. Symptoms, signs, side effects checklist. Psychopharmacol Bull. 1987;23: 322–323. 19. Taylor D, Sparshatt A, Varma S, et al. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ (Clin Res Ed). 2014; 348:g1888. 20. Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109–120.
338
www.psychopharmacology.com
Antidepressant Effects of Open Label Treatment With Coenzyme Q10 in Geriatric Bipolar Depression To the Editors: lthough bipolar disorder (BD) often presents in young adulthood, most individuals experience recurrent mood episodes, psychosocial deficits, and high utilization of health services that persist into later life.1 Bipolar depression represents the predominant and least successfully treated phase of this illness. Individuals with BD spend more time ill with depressive symptoms than with manic/hypomanic or with cycling/mixed symptoms,2–4 and the proportion of time spent in depressive episodes to time spent in manic episodes increases with age. The few medications (quetiapine, lurasidone, and olanzapinefluoxetine) that are US Food and Drug Administration approved for treatment of bipolar depression were studied in predominantly middle adult–aged cohorts. The clinical management of bipolar disorder in later life is also complicated by medical comorbidity, cognitive impairment, and polypharmacy.5 Furthermore, the neurobiological mechanisms that underlie bipolar depression may change with age, and resistance to current treatments is high.6,7 Over the past decade, there has been increasing evidence8 that implicates alterations in bioenergetic metabolism and enhanced oxidative stress in the neurobiology of bipolar disorder.9 Although the degree of mitochondrial dysfunction does not produce a substantial systemic metabolic disorder, it is likely sufficient to impact the CNS, as the brain requires 20-fold the energy production of the rest of the body.9 Furthermore, the efficiency of mitochondrial energy production declines with age, an effect seen both in central nervous system and peripheral tissue. Successful treatment strategies for late life bipolar disorder may depend on developing novel ways to address reduced mitochondrial adenosine triphosphate production. Coenzyme Q10 (CoQ10) is present in the phospholipid bilayers of mitochondria,10 shuttling electrons within the mitochondrial electron transport chain to generate adenosine triphosphate and serving as a potent antioxidant.11 CoQ10has been studied as a treatment for disorders implicating mitochondrial impairment, including congestive heart failure, diabetes, and degenerative neurological conditions.12–15 We now present the results from an open-label study of CoQ10 (added to existing treatment at a dosage of 800 mg/d for 4 weeks) for the treatment of older adults with a current episode
A
of bipolar depression. We hypothesized that CoQ10 would reduce depressive symptoms as measured by the Montgomery Asberg Depression Rating Scale (MADRS). After institutional review board approval, subjects were recruited to participate in 2 studies investigating the bioenergetic effects of CoQ10 using a 31P-MRS protocol at 4 Tesla (T)16 (Forester, unpublished). Subjects met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for bipolar disorder, type I or II, current episode depressed, and were excluded with any previous or current comorbid Axis I disorder, unstable medical illness, untreated thyroid dysfunction, a history of substance abuse within the past year, Young Mania Rating Scale (YMRS) score of higher than 6, or MADRS lower than 18. Subjects with bipolar depression continued concomitant psychotropic medication during the study, but dosages were left unchanged for the 2 weeks before treatment initiation and during the 4-week study period unless a change in dosage was clinically necessary. At all study visits (baseline and Weeks 2 and 4 of treatment), subjects had a psychiatric interview and completed MADRS and YMRS ratings and drug accountability assessments. Adverse events and vital signs were also recorded. The dosage of CoQ10 was started at 400 mg daily for 2 weeks and then titrated up to a dosage of 800 mg once daily for Weeks 3 and 4. The dose escalation schedule was modified if tolerability issues developed. At the final study visit, CoQ10 was tapered to 400 mg/d for 3 days and then discontinued, and subjects were referred for ongoing clinical treatment. Multiple degree of freedom comparison of MADRS between baseline and follow-up scores and single degree of freedom comparisons between baseline and follow-up scores at Weeks 2 and 4 were performed in the presence of an overall association significant at the α level of 0.05. Age, sex, and statin use were each added separately as covariates to assess for their individual associations with changes in MADRS ratings. Repeated-measures linear regression models were fit using the PROC MIXED routine for SAS statistical software (version 9.1.3). All statistical tests were 2 sided and performed at the α = 0.05 significance level. Eighty older adults, age 55 years and older, were screened, and a total of 32 individuals with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, bipolar disorder, type I or II, current episode depressed (BPD) signed informed consent. Eighteen subjects completed the 4-week trial of CoQ10, nine did not meet inclusion criteria, and
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
TABLE 1. Concomitant Psychotropic Medications, Mean Daily Dose Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Psychotropic Meds (Daily Dose) Donepezil 10 mg, lamotrigine 150 mg Divalproex 750 mg, quetiapine 100/100/200, Omega 3 FA 2000mg, lorazepam 1 mg PRN Lamotrigine 87.5 mg Omega 3 FA (unknown dose) Paroxetine 40 mg, venlafaxine 150 mg, trazadone 50 mg, buspirone 80 mg Venlafaxine 75 mg, lithium 1500 mg, bupropion 300 mg lithium 600 mg, escitalopram 20 mg Venlafaxine 150 mg, divalproex 250 mg, bupropion 250 mg, methylphenidate 25 mg lithium1200 mg, lamotrigine 100 mg Oxcarbazepine 1800 mg, olanzapine 25 mg, lorazepam 0.5 mg/0.5 mg PRN Paroxetine 25 mg None Zolpidem 10 mg, clonazepam 1 mg, Omega 3 FA 1000 mg Quetiapine 200 mg, lamotrigine 200 mg, trazadone 50 mg, methylphenidate 20 mg, clonazepam 1 mg Lamotrigine 50 mg Desvenlafaxine 100 mg, oxcarbazepine 900 mg, clonazepam 1 mg None Omega 3 FA 240 mg, gabapentin 2400 mg, lamotrigine 200 mg, venlafaxine 37.5 mg, quetiapine100 mg Citalopram 40 mg, lamotrigine 100 mg
four withdrew for reasons unrelated to study protocol and 1 withdrew during the trial due to diarrhea. The sample included 19 participants (18 non-Hispanic white and 1 African American subjects). Ten of the 19 subjects were male, with a mean age of 63 ± 6.54 years (age range, 56-78 years). The mean age of onset of bipolar disorder was 26.7 ± 18.0 years (with age of first depressive episode 27 ± 18.2 years and age of first manic episode 34.6 ± 16.9 years). Baseline mood measures indicated moderate depression severity (MADRS score mean 23.89 ± 6.90) and low manic symptom severity (YMRS score mean, 4.26 ± 3.68). Concomitant psychotropic medication and mean daily dose by subject is provided in Table 1. There was a significant reduction in total MADRS score from baseline through Week 4 of the study after covarying for age, sex, and statin use (F2,34 = 8.09; P = 0.001). A post hoc analysis of change from baseline to Week 2 was marginally significant (t34 = −1.85; P = 0.07), whereas the change from baseline to Week 4 was strongly significant (t34 = −4.02; P < 0.001). Furthermore, a secondary exploratory analysis of the change in a 3-factor symptom domain model of the MADRS14 indicated a significant decline over 4 weeks in the retardation factor that includes symptoms of lassitude, inability to feel, apparent sadness, and concentration difficulties. CoQ10 was well tolerated by study participants. Only 1 subject
discontinued treatment before study completion because of an adverse effect (diarrhea developed within 3 days of initiating treatment with CoQ10 at 400 mg/d and resolved shortly after discontinuation of CoQ10). There were no serious or unexpected adverse events. Other AEs not felt to be related to study medication included a recurrence of atrial fibrillation, constipation, hair loss, “eye pain,” headaches not associated with changes in vision, loose stools, reduced appetite (each occurred in 1 subject), and mild nausea (4 subjects).
DISCUSSION Findings of putative antidepressant effects of open-label CoQ10 in a cohort of older adults with bipolar depression suggest that mitochondrial enhancing therapies may play a role in the treatment of affective illness. Study results also suggest specific symptom domains, such as lassitude, apparent sadness, and poor concentration, may preferentially respond to such energy-enhancing therapies. Although limited by an open label design and a small study sample and allowing for inclusion of concomitant medications, these findings provide initial proof-of-concept scientific evidence for antidepressant effects of the mitochondrial energy-enhancing and antioxidant compound CoQ10 when used as an adjunctive therapy for older adults with bipolar depression.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
A neuroprogressive hypothesis of bipolar disorder that implicates the neurobiological mechanisms of inflammation, glutamatergic excitotoxicity, oxidative stress, and mitochondrial dysfunction in the pathophysiology of neuronal damage and cognitive impairment in bipolar disorder with advancing age has been developed.17 Previous treatment studies that included aging cohorts of individuals with bipolar depression were not designed to address these underlying neurobiological mechanisms. CoQ10 has both antioxidant and mitochondrial enhancing effects, providing a neurobiological rationale for adjunctive use of CoQ10 in clinical studies of bipolar depression. Confirmation of these findings using a double-blinded randomized design is essential before the use of CoQ10 as a treatment for bipolar depression could be recommended. ACKNOWLEDGMENT The work presented in this publication was completed at the Geriatric Psychiatry Research Program located in Belmont, MA. Support for the publication was granted by the National Institutes of Mental Health (K23 MH077287), The Brain and Behavior Foundation (formerly NARSAD), and the Rogers Family Foundation. Data were presented at the Annual Meetings of the American Association for Geriatric Psychiatry and the International College of Geriatric Psychoneuropharmacology. Coenzyme Q10 tablets were provided by NBTY, Inc. with assistance from Kyowa Hakko USA.
AUTHOR DISCLOSURE INFORMATION Dr Forester has served as a consultant within the past 3 years for Sunovion Pharmaceuticals, Inc., and he has grant support now from AssureRx. The other authors declare no conflicts of interest.
Brent P. Forester, MD, MSc Geriatric Psychiatry Research Program McLean Hospital Belmont, MA and Harvard Medical School Department of Psychiatry Boston, MA [email protected]
David G. Harper, PhD Geriatric Psychiatry Research Program McLean Hospital Belmont, MA and Harvard Medical School Department of Psychiatry Boston, MA www.psychopharmacology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
339
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
Letters to the Editors
Joanna Georgakas Geriatric Psychiatry Research Program McLean Hospital Belmont, MA
Caitlin Ravichandran, PhD Harvard Medical School Department of Psychiatry Boston, MA and McLean Hospital Laboratory for Psychiatric Biostatistics Belmont, MA
Nethra Madurai Geriatric Psychiatry Research Program McLean Hospital Belmont, MA
Bruce M. Cohen, MD, PhD Harvard Medical School Department of Psychiatry Boston, MA and Shervert Frazier Research Institute McLean Hospital Belmont, MA
REFERENCES 1. Bartels SJ, Forester B, Miles KM, et al. Mental health service use by elderly patients with bipolar disorder and unipolar major depression. Am J Geriatr Psychiatry. 2000;8:160–166. 2. Kalin NH. Management of the depressive component of bipolar disorder. Depress Anxiety. 1996;4:190–198. 3. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003; 60:261–269. 4. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530–537. 5. Young RC, Gyulai L, Mulsant BH, et al. Pharmacotherapy of bipolar disorder in old age: review and recommendations. Am J Geriatr Psychiatry. 2004;12:342–357. 6. Gitlin MJ, Swendsen J, Heller TL, et al. Relapse and impairment in bipolar disorder. Am J Psychiatry. 1995;152:1635–1640. 7. Konradi C, Eaton M, MacDonald ML, et al. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61:300–308. 8. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry. 2005;10:900–919. 9. Cataldo AM, McPhie DL, Lange NT, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol. 2010;177:575–585. 10. Battino M, Ferri E, Gorini A, et al. Natural distribution and occurrence of coenzyme Q homologues. Membr Biochem. 1990;9:179–190.
340
www.psychopharmacology.com
11. Beyer RE. An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol. 1992;70: 390–403. 12. Kasparova S, Sumbalova Z, Horecky J, et al. New magnetic resonance spectroscopy biomarker for monitoring neurodegenerative diseases: animal models. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149:373–376. 13. Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009;5:597–610. 14. Shults CW, Haas R. Clinical trials of coenzyme Q10 in neurological disorders. Biofactors 2005;25:117–126. 15. Singh RB, Neki NS, Kartikey K, et al. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction. Mol Cell Biochem. 2003;246:75–82. 16. Forester BP, Zuo CS, Ravichandran C, et al. Coenzyme q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatr Neurol. 2012;25:43–50. 17. Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35: 804–817.
Silymarin Treatment of Obsessive-Compulsive Spectrum Disorders
CASE 1
To the Editors: bsessive-compulsive disorder (OCD) and body-focused repetitive behaviors have recently been grouped in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, under the larger category of “obsessive-compulsive and related disorders.” The hallmark of these disorders is the engagement in repetitive, functionally impairing habits that are difficult to suppress. Current neurobiological models of this category of disorders emphasize the likely involvement of excessive habit generation from evolutionarily ancient parts of the brain (the striatum) coupled with a lack of sufficient top-down control over these habits from cortical regions (particularly the frontal lobes).1 Pharmacotherapy options for these disorders include serotonin reuptake inhibitors, which have demonstrated success for OCD,2 and glutamatergic agents (eg, N-acetylcysteine),
O
which have shown early promise for the treatment of body-focused repetitive behaviors.3,4 Given the fact that many individuals show limited to negligible response to available pharmacotherapies, new treatments are needed. Obsessive-compulsive disorder is a neuropsychiatric disorder characterized by obsessions and/or compulsions that are distressing, time consuming, or significantly impairing.5 It is the fourth most common psychiatric illness with a lifetime prevalence of 1% to 3%.6,7 Trichotillomania is defined as the recurrent pulling of hair, and although exact prevalence estimates are unknown, trichotillomania seems to be relatively common, with estimated lifetime prevalence rates of 1% to 3.4%.8 Pathological nail biting has been defined as biting nails “beyond the free edge with nail margin below the soft tissue border”9 and often produces lowered self-esteem, chronic subungual infections, and gingival swelling.10 Because effective pharmacological treatments are needed, we treated three cases of OCD and related disorders with Silymarin, which is derived from the milk thistle plant and widely used to treat liver diseases. Silymarin is composed of six major flavonolignans, which have been shown to have anti-oxidative and antiinflammatory properties11,12 and may have a beneficial effect on dopamine functioning.13 Milk thistle is generally well tolerated, although mild nausea, diarrhea, and indigestion are possible side effects.
Ms J is an 18-year-old white college student who presented to a university medical research center for treatment of trichotillomania. Examination revealed no history of substance abuse, psychosis, mania, OCD, or anxiety disorders. Ms J reported that hair pulling began at age 14 and worsened during the past year. She reported pulling her eyebrows for approximately 30–45 minutes each day and experienced significant social impairment (eg, she never dated) because of the hair pulling. Her score on the National Institute of Mental Health Trichotillomania Symptom Severity (NIMH-TSS) scale was 11 (indicating moderate severity). Previous treatments included 4 months of weekly habit reversal therapy with minimal benefit and with no pulling-free days. At the time of presentation, Ms J was not taking other medications. Treatment with milk thistle began at 150 mg twice a day. After 6 weeks, the patient reported that she had gone 4 consecutive days without pulling. After 4 months, Ms J reported almost complete cessation of pulling (2–3 minutes
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors 6. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(5): 561–566. 7. Levitan MG, Papelbaum M, Nardi AE. A review of preliminary observations on agomelatine in the treatment of anxiety disorders. Exp Clin Psychopharmacol. 2012;20(6):504–509. 8. Kasper S, Hamon M. Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant with an innovative mechanism of action. World J Biol Psychiatry. 2009;10(2):117–126. 9. Fornaro M. Agomelatine in the treatment of panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):286–287. 10. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P) New York: Biometrics Research, New York State Psychiatric Institute; 2002. 11. Furukawa TA, Katherine Shear M, Barlow DH, et al. Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. Depress Anxiety. 2009;26(10):922–929. 12. Shear MK, Brown TA, Barlow DH, et al. Multicenter collaborative panic disorder severity scale. Am J Psychiatry. 1997;154:1571–1575. 13. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. 14. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory—II. San Antonio, TX: Psychological Corporation; 1996. 15. Beck AT, Steer RA. Beck Anxiety Inventory Manual. San Antonio, TX: Psychological Corporation; 1993. 16. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483. 17. Leon AC, Shear MK, Portera L, et al. Assessing impairment in patients with panic disorder: the Sheehan Disability Scale. Soc Psychiatry Psychiatr Epidemiol. 1992; 27(2):78–82. 18. Fawcett S. Symptoms, signs, side effects checklist. Psychopharmacol Bull. 1987;23: 322–323. 19. Taylor D, Sparshatt A, Varma S, et al. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ (Clin Res Ed). 2014; 348:g1888. 20. Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109–120.
338
www.psychopharmacology.com
Antidepressant Effects of Open Label Treatment With Coenzyme Q10 in Geriatric Bipolar Depression To the Editors: lthough bipolar disorder (BD) often presents in young adulthood, most individuals experience recurrent mood episodes, psychosocial deficits, and high utilization of health services that persist into later life.1 Bipolar depression represents the predominant and least successfully treated phase of this illness. Individuals with BD spend more time ill with depressive symptoms than with manic/hypomanic or with cycling/mixed symptoms,2–4 and the proportion of time spent in depressive episodes to time spent in manic episodes increases with age. The few medications (quetiapine, lurasidone, and olanzapinefluoxetine) that are US Food and Drug Administration approved for treatment of bipolar depression were studied in predominantly middle adult–aged cohorts. The clinical management of bipolar disorder in later life is also complicated by medical comorbidity, cognitive impairment, and polypharmacy.5 Furthermore, the neurobiological mechanisms that underlie bipolar depression may change with age, and resistance to current treatments is high.6,7 Over the past decade, there has been increasing evidence8 that implicates alterations in bioenergetic metabolism and enhanced oxidative stress in the neurobiology of bipolar disorder.9 Although the degree of mitochondrial dysfunction does not produce a substantial systemic metabolic disorder, it is likely sufficient to impact the CNS, as the brain requires 20-fold the energy production of the rest of the body.9 Furthermore, the efficiency of mitochondrial energy production declines with age, an effect seen both in central nervous system and peripheral tissue. Successful treatment strategies for late life bipolar disorder may depend on developing novel ways to address reduced mitochondrial adenosine triphosphate production. Coenzyme Q10 (CoQ10) is present in the phospholipid bilayers of mitochondria,10 shuttling electrons within the mitochondrial electron transport chain to generate adenosine triphosphate and serving as a potent antioxidant.11 CoQ10has been studied as a treatment for disorders implicating mitochondrial impairment, including congestive heart failure, diabetes, and degenerative neurological conditions.12–15 We now present the results from an open-label study of CoQ10 (added to existing treatment at a dosage of 800 mg/d for 4 weeks) for the treatment of older adults with a current episode
A
of bipolar depression. We hypothesized that CoQ10 would reduce depressive symptoms as measured by the Montgomery Asberg Depression Rating Scale (MADRS). After institutional review board approval, subjects were recruited to participate in 2 studies investigating the bioenergetic effects of CoQ10 using a 31P-MRS protocol at 4 Tesla (T)16 (Forester, unpublished). Subjects met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for bipolar disorder, type I or II, current episode depressed, and were excluded with any previous or current comorbid Axis I disorder, unstable medical illness, untreated thyroid dysfunction, a history of substance abuse within the past year, Young Mania Rating Scale (YMRS) score of higher than 6, or MADRS lower than 18. Subjects with bipolar depression continued concomitant psychotropic medication during the study, but dosages were left unchanged for the 2 weeks before treatment initiation and during the 4-week study period unless a change in dosage was clinically necessary. At all study visits (baseline and Weeks 2 and 4 of treatment), subjects had a psychiatric interview and completed MADRS and YMRS ratings and drug accountability assessments. Adverse events and vital signs were also recorded. The dosage of CoQ10 was started at 400 mg daily for 2 weeks and then titrated up to a dosage of 800 mg once daily for Weeks 3 and 4. The dose escalation schedule was modified if tolerability issues developed. At the final study visit, CoQ10 was tapered to 400 mg/d for 3 days and then discontinued, and subjects were referred for ongoing clinical treatment. Multiple degree of freedom comparison of MADRS between baseline and follow-up scores and single degree of freedom comparisons between baseline and follow-up scores at Weeks 2 and 4 were performed in the presence of an overall association significant at the α level of 0.05. Age, sex, and statin use were each added separately as covariates to assess for their individual associations with changes in MADRS ratings. Repeated-measures linear regression models were fit using the PROC MIXED routine for SAS statistical software (version 9.1.3). All statistical tests were 2 sided and performed at the α = 0.05 significance level. Eighty older adults, age 55 years and older, were screened, and a total of 32 individuals with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, bipolar disorder, type I or II, current episode depressed (BPD) signed informed consent. Eighteen subjects completed the 4-week trial of CoQ10, nine did not meet inclusion criteria, and
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
TABLE 1. Concomitant Psychotropic Medications, Mean Daily Dose Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Psychotropic Meds (Daily Dose) Donepezil 10 mg, lamotrigine 150 mg Divalproex 750 mg, quetiapine 100/100/200, Omega 3 FA 2000mg, lorazepam 1 mg PRN Lamotrigine 87.5 mg Omega 3 FA (unknown dose) Paroxetine 40 mg, venlafaxine 150 mg, trazadone 50 mg, buspirone 80 mg Venlafaxine 75 mg, lithium 1500 mg, bupropion 300 mg lithium 600 mg, escitalopram 20 mg Venlafaxine 150 mg, divalproex 250 mg, bupropion 250 mg, methylphenidate 25 mg lithium1200 mg, lamotrigine 100 mg Oxcarbazepine 1800 mg, olanzapine 25 mg, lorazepam 0.5 mg/0.5 mg PRN Paroxetine 25 mg None Zolpidem 10 mg, clonazepam 1 mg, Omega 3 FA 1000 mg Quetiapine 200 mg, lamotrigine 200 mg, trazadone 50 mg, methylphenidate 20 mg, clonazepam 1 mg Lamotrigine 50 mg Desvenlafaxine 100 mg, oxcarbazepine 900 mg, clonazepam 1 mg None Omega 3 FA 240 mg, gabapentin 2400 mg, lamotrigine 200 mg, venlafaxine 37.5 mg, quetiapine100 mg Citalopram 40 mg, lamotrigine 100 mg
four withdrew for reasons unrelated to study protocol and 1 withdrew during the trial due to diarrhea. The sample included 19 participants (18 non-Hispanic white and 1 African American subjects). Ten of the 19 subjects were male, with a mean age of 63 ± 6.54 years (age range, 56-78 years). The mean age of onset of bipolar disorder was 26.7 ± 18.0 years (with age of first depressive episode 27 ± 18.2 years and age of first manic episode 34.6 ± 16.9 years). Baseline mood measures indicated moderate depression severity (MADRS score mean 23.89 ± 6.90) and low manic symptom severity (YMRS score mean, 4.26 ± 3.68). Concomitant psychotropic medication and mean daily dose by subject is provided in Table 1. There was a significant reduction in total MADRS score from baseline through Week 4 of the study after covarying for age, sex, and statin use (F2,34 = 8.09; P = 0.001). A post hoc analysis of change from baseline to Week 2 was marginally significant (t34 = −1.85; P = 0.07), whereas the change from baseline to Week 4 was strongly significant (t34 = −4.02; P < 0.001). Furthermore, a secondary exploratory analysis of the change in a 3-factor symptom domain model of the MADRS14 indicated a significant decline over 4 weeks in the retardation factor that includes symptoms of lassitude, inability to feel, apparent sadness, and concentration difficulties. CoQ10 was well tolerated by study participants. Only 1 subject
discontinued treatment before study completion because of an adverse effect (diarrhea developed within 3 days of initiating treatment with CoQ10 at 400 mg/d and resolved shortly after discontinuation of CoQ10). There were no serious or unexpected adverse events. Other AEs not felt to be related to study medication included a recurrence of atrial fibrillation, constipation, hair loss, “eye pain,” headaches not associated with changes in vision, loose stools, reduced appetite (each occurred in 1 subject), and mild nausea (4 subjects).
DISCUSSION Findings of putative antidepressant effects of open-label CoQ10 in a cohort of older adults with bipolar depression suggest that mitochondrial enhancing therapies may play a role in the treatment of affective illness. Study results also suggest specific symptom domains, such as lassitude, apparent sadness, and poor concentration, may preferentially respond to such energy-enhancing therapies. Although limited by an open label design and a small study sample and allowing for inclusion of concomitant medications, these findings provide initial proof-of-concept scientific evidence for antidepressant effects of the mitochondrial energy-enhancing and antioxidant compound CoQ10 when used as an adjunctive therapy for older adults with bipolar depression.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editors
A neuroprogressive hypothesis of bipolar disorder that implicates the neurobiological mechanisms of inflammation, glutamatergic excitotoxicity, oxidative stress, and mitochondrial dysfunction in the pathophysiology of neuronal damage and cognitive impairment in bipolar disorder with advancing age has been developed.17 Previous treatment studies that included aging cohorts of individuals with bipolar depression were not designed to address these underlying neurobiological mechanisms. CoQ10 has both antioxidant and mitochondrial enhancing effects, providing a neurobiological rationale for adjunctive use of CoQ10 in clinical studies of bipolar depression. Confirmation of these findings using a double-blinded randomized design is essential before the use of CoQ10 as a treatment for bipolar depression could be recommended. ACKNOWLEDGMENT The work presented in this publication was completed at the Geriatric Psychiatry Research Program located in Belmont, MA. Support for the publication was granted by the National Institutes of Mental Health (K23 MH077287), The Brain and Behavior Foundation (formerly NARSAD), and the Rogers Family Foundation. Data were presented at the Annual Meetings of the American Association for Geriatric Psychiatry and the International College of Geriatric Psychoneuropharmacology. Coenzyme Q10 tablets were provided by NBTY, Inc. with assistance from Kyowa Hakko USA.
AUTHOR DISCLOSURE INFORMATION Dr Forester has served as a consultant within the past 3 years for Sunovion Pharmaceuticals, Inc., and he has grant support now from AssureRx. The other authors declare no conflicts of interest.
Brent P. Forester, MD, MSc Geriatric Psychiatry Research Program McLean Hospital Belmont, MA and Harvard Medical School Department of Psychiatry Boston, MA [email protected]
David G. Harper, PhD Geriatric Psychiatry Research Program McLean Hospital Belmont, MA and Harvard Medical School Department of Psychiatry Boston, MA www.psychopharmacology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
339
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
Letters to the Editors
Joanna Georgakas Geriatric Psychiatry Research Program McLean Hospital Belmont, MA
Caitlin Ravichandran, PhD Harvard Medical School Department of Psychiatry Boston, MA and McLean Hospital Laboratory for Psychiatric Biostatistics Belmont, MA
Nethra Madurai Geriatric Psychiatry Research Program McLean Hospital Belmont, MA
Bruce M. Cohen, MD, PhD Harvard Medical School Department of Psychiatry Boston, MA and Shervert Frazier Research Institute McLean Hospital Belmont, MA
REFERENCES 1. Bartels SJ, Forester B, Miles KM, et al. Mental health service use by elderly patients with bipolar disorder and unipolar major depression. Am J Geriatr Psychiatry. 2000;8:160–166. 2. Kalin NH. Management of the depressive component of bipolar disorder. Depress Anxiety. 1996;4:190–198. 3. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003; 60:261–269. 4. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530–537. 5. Young RC, Gyulai L, Mulsant BH, et al. Pharmacotherapy of bipolar disorder in old age: review and recommendations. Am J Geriatr Psychiatry. 2004;12:342–357. 6. Gitlin MJ, Swendsen J, Heller TL, et al. Relapse and impairment in bipolar disorder. Am J Psychiatry. 1995;152:1635–1640. 7. Konradi C, Eaton M, MacDonald ML, et al. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61:300–308. 8. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry. 2005;10:900–919. 9. Cataldo AM, McPhie DL, Lange NT, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol. 2010;177:575–585. 10. Battino M, Ferri E, Gorini A, et al. Natural distribution and occurrence of coenzyme Q homologues. Membr Biochem. 1990;9:179–190.
340
www.psychopharmacology.com
11. Beyer RE. An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol. 1992;70: 390–403. 12. Kasparova S, Sumbalova Z, Horecky J, et al. New magnetic resonance spectroscopy biomarker for monitoring neurodegenerative diseases: animal models. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149:373–376. 13. Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009;5:597–610. 14. Shults CW, Haas R. Clinical trials of coenzyme Q10 in neurological disorders. Biofactors 2005;25:117–126. 15. Singh RB, Neki NS, Kartikey K, et al. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction. Mol Cell Biochem. 2003;246:75–82. 16. Forester BP, Zuo CS, Ravichandran C, et al. Coenzyme q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatr Neurol. 2012;25:43–50. 17. Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35: 804–817.
Silymarin Treatment of Obsessive-Compulsive Spectrum Disorders
CASE 1
To the Editors: bsessive-compulsive disorder (OCD) and body-focused repetitive behaviors have recently been grouped in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, under the larger category of “obsessive-compulsive and related disorders.” The hallmark of these disorders is the engagement in repetitive, functionally impairing habits that are difficult to suppress. Current neurobiological models of this category of disorders emphasize the likely involvement of excessive habit generation from evolutionarily ancient parts of the brain (the striatum) coupled with a lack of sufficient top-down control over these habits from cortical regions (particularly the frontal lobes).1 Pharmacotherapy options for these disorders include serotonin reuptake inhibitors, which have demonstrated success for OCD,2 and glutamatergic agents (eg, N-acetylcysteine),
O
which have shown early promise for the treatment of body-focused repetitive behaviors.3,4 Given the fact that many individuals show limited to negligible response to available pharmacotherapies, new treatments are needed. Obsessive-compulsive disorder is a neuropsychiatric disorder characterized by obsessions and/or compulsions that are distressing, time consuming, or significantly impairing.5 It is the fourth most common psychiatric illness with a lifetime prevalence of 1% to 3%.6,7 Trichotillomania is defined as the recurrent pulling of hair, and although exact prevalence estimates are unknown, trichotillomania seems to be relatively common, with estimated lifetime prevalence rates of 1% to 3.4%.8 Pathological nail biting has been defined as biting nails “beyond the free edge with nail margin below the soft tissue border”9 and often produces lowered self-esteem, chronic subungual infections, and gingival swelling.10 Because effective pharmacological treatments are needed, we treated three cases of OCD and related disorders with Silymarin, which is derived from the milk thistle plant and widely used to treat liver diseases. Silymarin is composed of six major flavonolignans, which have been shown to have anti-oxidative and antiinflammatory properties11,12 and may have a beneficial effect on dopamine functioning.13 Milk thistle is generally well tolerated, although mild nausea, diarrhea, and indigestion are possible side effects.
Ms J is an 18-year-old white college student who presented to a university medical research center for treatment of trichotillomania. Examination revealed no history of substance abuse, psychosis, mania, OCD, or anxiety disorders. Ms J reported that hair pulling began at age 14 and worsened during the past year. She reported pulling her eyebrows for approximately 30–45 minutes each day and experienced significant social impairment (eg, she never dated) because of the hair pulling. Her score on the National Institute of Mental Health Trichotillomania Symptom Severity (NIMH-TSS) scale was 11 (indicating moderate severity). Previous treatments included 4 months of weekly habit reversal therapy with minimal benefit and with no pulling-free days. At the time of presentation, Ms J was not taking other medications. Treatment with milk thistle began at 150 mg twice a day. After 6 weeks, the patient reported that she had gone 4 consecutive days without pulling. After 4 months, Ms J reported almost complete cessation of pulling (2–3 minutes
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
