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Clinical and Research Reports   |    
Agomelatine Treatment of Major Depressive Disorder in Parkinson's Disease: A Case Series
Domenico De Berardis, M.D., Ph.D.; Michele Fornaro, M.D.; Nicola Serroni, M.D.; Luigi Olivieri, M.D.; Stefano Marini, M.D.; Francesco Saverio Moschetta, M.D.; Venkataramanujam Srinivasan, Ph.D.; Maurizio Assetta, M.D.; Alessandro Valchera, M.D.; Anatolia Salone, M.D., Ph.D.; Giovanni Martinotti, M.D., Ph.D.; Marco Onofrj, M.D.; Massimo Di Giannantonio, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:343-345. doi:10.1176/appi.neuropsych.12110286
View Author and Article Information

All authors have equally contributed to the present case series.

Conflicts of Interest and Source of Funding: The authors have no conflict of interest to declare.

From NHS, Dept. of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini,” Teramo, Italy (DDB, NS, LO, SM, FSM), Dept. of Neuroscience and Imaging, University “G. D’Annunzio,” Chieti, Italy (DDB, SM, AS, GM, MDG), Dept. of “Scienze della Formazione,” University of Catania, Italy (MF), Sri Sathya Sai Medical Educational and Research Foundation, Medical Sciences Research Study Center, Prasanthi Nilayam, Tamilnadu, India (VS), U.O.C. Neurology, Hospital “G. Mazzini,” ASL 4 Teramo, Italy (MA), Villa San Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy (AV), Dept. of Neuroscience and Imaging, Neurology, University “G. D’Annunzio,” Chieti, Italy (MO).

Send correspondence to Dr. De Berardis; e-mail: dodebera@aliceposta.it

Copyright © 2013 by the American Psychiatric Association

Received November 22, 2012; Revised March 21, 2013; Accepted April 08, 2013.

Major Depressive Disorder (MDD) is among the most frequent comorbidities occurring in the course of Parkinson’s disease (PD), and therefore, most PD patients receive antidepressant drugs. Agomelatine is a recently introduced antidepressant drug acting as an MT1/MT2 melatonergic receptor agonist and 5HT2C/5HT2B serotonergic antagonist. The aim of this case series was to evaluate the role of agomelatine in the treatment of MDD associated with PD.

Abstract Teaser
Figures in this Article

Major Depressive Disorder (MDD) is frequent as a comorbidity of Parkinson’s disease (PD), and therefore, it is not surprising that such patients receive antidepressants.13

Agomelatine is a recently introduced antidepressant drug acting as an MT1/MT2 melatonergic receptor agonist and 5HT2C/5HT2B serotonergic antagonist, indirectly promoting disinhibition of norepinephrinergic and dopaminergic transmissions at the frontal cortex, preventing a relative hypo-dopaminergia at the striatum.4,5 The efficacy of agomelatine in the treatment of MDD has been proven.6,7

The aim of this case series was to evaluate agomelatine in the treatment of MDD associated with PD.

Case #1: “DAG,” a 56-year-old housewife, was seen because of severe depressive symptoms, with anhedonia and insomnia lasting for 6 months Her symptoms had started 7 months earlier, after the death of her mother. She had been diagnosed with PD about 5 years earlier, when she was prescribed levodopa 150 mg qid and pergolide 1 mg tid. She underwent the following tests: the Unified Parkinson Disease Rating Scale (UPDRS):8 motor score, 9; the 17-item Hamilton Rating Scale for Depression (Ham-D):9 score, 32; the Mini-Mental State Exam (MMSE):10 score, 30; the Snaith-Hamilton Pleasure Scale (SHAPS):11 score, 11. Agomelatine 25 mg/day at bedtime was prescribed and increased to 50 mg/once per day after 2 weeks. After 4 weeks of therapy, we observed a significant improvement in symptoms (Ham-D: 20), without worsening of PD. After 8 weeks of therapy, she achieved remission (Ham-D: 7), with a significant decrease in anhedonia and complete restoration of sleep–wake cycle. No agomelatine adverse effects were observed.

Case #2: “DG,” a 58-year-old white-collar worker, was diagnosed with PD about 10 years earlier and was on levodopa 100 mg five times per day and pergolide 0.5 mg tid for approximately 2 years. The patient had had ongoing treatment with escitalopram 20 mg/day for depression and anxiety for almost 3 months, with some subjective reported worsening of parkinsonian symptoms. At our observation, the patient showed depressed mood, with spontaneous crying, anhedonia, daily hypersomnia, and nocturnal awakening. He underwent the following tests: UPDRS: motor score, 12; Ham-D: score, 33; MMSE: score, 29; SHAPS: score, 13. Agomelatine 25 mg/day at bedtime was prescribed in augmentation to escitalopram therapy. After 4 weeks of therapy, we observed a significant improvement in symptoms (Ham-D: 26), with a subjective improvement of PD. After 8 weeks of therapy, we obtained a response on the Ham-D (score: 15), No agomelatine/escitalopram combination adverse effects were observed except mild nausea.

Case #3: “FF,” a 45-year-old woman white-collar worker, was diagnosed with PD about 4 years earlier and was taking stable doses of levodopa 100 mg qid. At our first observation, the patient showed severe depressed mood, with anhedonia, psychomotor retardation, loss of energy, decreased appetite with loss of weight, initial and terminal insomnia with intra-sleep awakening, and suicidal thoughts. Her neurologist prescribed venlafaxine 150 mg/day, over about 2 months, without benefit. She underwent the following tests: UPDRS: motor score, 7; Ham-D: score, 35; MMSE: score, 30; SHAPS: score, 10. Venlafaxine was discontinued, and agomelatine was introduced at 25 mg at bedtime, increased to 50 mg after 3 weeks. After 8 weeks of therapy the patient gained a response (Ham-D: 12). No worsening of PD was observed. No agomelatine adverse effects were observed, except mild nausea and constipation.

All the patients provided informed consent to present these reports and were continuously monitored for liver functioning.12

To date, proven therapies for MDD in PD include nortriptyline, desipramine, selective serotonin reuptake inhibitors (SSRIs), and pramipexole as an alternative to antidepressant drugs.13 To our knowledge, this is the first report about agomelatine for the treatment of depression in PD.

About Case #1, the fact that the patient experienced a recent grief preceding the onset of the major depressive episode is in line with the hypothesis of a specific vulnerability of circadian rhythmicity upon intense stressors among patients with PD and/or MDD, thus favoring the agomelatine response.14,15

Concerning Case #2, the role of concomitant treatment of escitalopram, either on the impact of motor symptoms of PD or in the potential induction of anhedonia or apathy, is unclear. The supposed mechanism, should be the 5HT2A postsynaptic stimulation provided by this SSRI drug at the nigro-striatal pathway (motor symptoms) or meso-cortico-limbic level (anhedonia or even, possibly, suicidal symptomatology). It is possible that agomelatine-induced increase in dopamine and noradrenaline levels in the frontal cortex, combined with the restored serotonin transmission due to escitalopram, may explain the positive outcome observed in this case.16

Case #3 also poses some interesting clinical implications. Remarkably, venlafaxine is supposed to act essentially as a serotonergic-reuptake inhibitor in doses lower than 225 mg/day,9 which means that virtually no indirect dopaminergic disinhibition at the frontal cortex was produced.17 Also, as per the SSRI drugs, venlafaxine may have contributed to motor or anhedonic symptomatology due to 5HT2A stimulation, whereas agomelatine is somewhat neutral on this receptor subtype.18 In fact, unlike other antidepressants, agomelatine does not interfere with 5HT2A receptor functioning.19 This may explain why agomelatine was effective in Case #3, whereas venlafaxine was not.

However, concerning all three cases, it is also possible to hypothesize that agomelatine-induced blockade of 5HT2C receptors may have reinforced fronto-cortical adrenergic and dopaminergic transmission, thus leading to improvement in depressive symptoms and anhedonia.17,20 Moreover, the positive effect of agomelatine may be further enhanced because of its efficacy in normalizing disturbances of circadian rhythms by means of the restoring of regular melatonergic activity in both substantia nigra and the amygdala.21

The observed improvement in the patients’ sleep disturbances after agomelatine introduction may have played a role in improvement of psychiatric’ status, as it has been demonstrated that patients with PD may show several sleep–wake disturbances, suggesting a potential alteration of circadian rhythms.22 Moreover, the presence of depression may further worsen the circadian rhythm disturbances.23 On the basis of such observations, it is also possible to hypothesize that the restoration of circadian rhythms, such as the improvement of sleep efficiency (in all three cases), together with the disappearance of intra-sleep awakening (especially in Cases #2 and #3), through MT1 and MT2 agonism of agomelatine, may have contributed to improving symptomatology.

Veazey  C;  Aki  SO;  Cook  KF  et al:  Prevalence and treatment of depression in Parkinson’s disease.  J Neuropsychiatry Clin Neurosci 2005; 17:310–323
[CrossRef] | [PubMed]
 
Weintraub  D;  Taraborelli  D;  Morales  KH  et al:  Escitalopram for major depression in Parkinson’s disease: an open-label, flexible-dosage study.  J Neuropsychiatry Clin Neurosci 2006; 18:377–383
[CrossRef] | [PubMed]
 
Lauterbach  EC;  Victoroff  J;  Coburn  KL  et al:  Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.  J Neuropsychiatry Clin Neurosci 2010; 22:8–18
[CrossRef] | [PubMed]
 
Fornaro  M;  Prestia  D;  Colicchio  S  et al:  A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation.  Curr Neuropharmacol 2010; 8:287–304
[CrossRef] | [PubMed]
 
De Berardis  D;  Di Iorio  G;  Acciavatti  T  et al:  The emerging role of melatonin agonists in the treatment of major depression: focus on agomelatine.  CNS Neurol Disord Drug Targets 2011; 10:119–132
[CrossRef] | [PubMed]
 
Martinotti  G;  Sepede  G;  Gambi  F  et al:  Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study.  J Clin Psychopharmacol 2012; 32:487–491
[CrossRef] | [PubMed]
 
Srinivasan  V;  Zakaria  R;  Othman  Z  et al:  Agomelatine in depressive disorders: its novel mechanisms of action.  J Neuropsychiatry Clin Neurosci 2012; 24:290–308
[CrossRef] | [PubMed]
 
Members of the UPDRS Development Committee:  Unified Parkinson’s Disease Rating Scale in Recent Developments in Parkinson’s Disease . Edited by Fahn  S;  Marsden  CD;  Calne  DB  et al.  Florham Park, NJ,  Macmillan Health Care Information, 1987
 
Hamilton  M:  Development of a rating scale for primary depressive illness.  Br J Soc Clin Psychol 1967; 6:278–296
[CrossRef] | [PubMed]
 
Folstein  MF;  Folstein  SE;  McHugh  PR:  “Mini-Mental State:” a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res 1975; 12:189–198
[CrossRef] | [PubMed]
 
Snaith  RP;  Hamilton  M;  Morley  S  et al:  A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale.  Br J Psychiatry 1995; 167:99–103
[CrossRef] | [PubMed]
 
European Medicines Agency European Public Assessment Report. Valdoxan, 2012; available at http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000915/human_med_001123.jsp&mid=WC0b01ac058001d124; accessed Oct 28, 2012
 
Barone  P:  Treatment of depressive symptoms in Parkinson’s disease.  Eur J Neurol 2011; 18(Suppl 1):11–15
[CrossRef] | [PubMed]
 
Meerlo  P;  Sgoifo  A;  Turek  FW:  The effects of social defeat and other stressors on the expression of circadian rhythms.  Stress 2002; 5:15–22
[CrossRef] | [PubMed]
 
O’Connor  MF;  Wellisch  DK;  Stanton  AL  et al:  Diurnal cortisol in complicated and non-complicated grief: slope differences across the day.  Psychoneuroendocrinology 2012; 37:725–728
[CrossRef] | [PubMed]
 
De Berardis D, Serroni N, Marini S, et al. Agomelatine augmentation of escitalopram therapy in treatment-resistant, obsessive-compulsive disorder: a case report. Case Rep Psychiatry 2012:642752
 
Debonnel  G;  Saint-André  E;  Hébert  C  et al:  Differential physiological effects of a low dose and high doses of venlafaxine in major depression.  Int J Neuropsychopharmacol 2007; 10:51–61
[CrossRef] | [PubMed]
 
Srinivasan  V;  De Berardis  D;  Shillcutt  SD  et al:  Role of melatonin in mood disorders and the antidepressant effects of agomelatine.  Expert Opin Investig Drugs 2012; 21:1503–1522
[CrossRef] | [PubMed]
 
Di Giannantonio  M;  Di Iorio  G;  Guglielmo  R  et al:  Major depressive disorder, anhedonia, and agomelatine: an open-label study.  J Biol Regul Homeost Agents 2011; 25:109–114
[PubMed]
 
Di Giannantonio  M;  Martinotti  G:  Anhedonia and major depression: the role of agomelatine.  Eur Neuropsychopharmacol 2012; 22(Suppl 3):S505–S510
[CrossRef] | [PubMed]
 
Adi  N;  Mash  DC;  Ali  Y  et al:  Melatonin MT1 and MT2 receptor expression in Parkinson’s disease.  Med Sci Monit 2010; 16:BR61–BR67
[PubMed]
 
Bruin  VM;  Bittencourt  LR;  Tufik  S:  Sleep–wake disturbances in Parkinson’s disease: current evidence regarding diagnostic and therapeutic decisions.  Eur Neurol 2012; 67:257–267
[CrossRef] | [PubMed]
 
Suzuki  K;  Miyamoto  T;  Miyamoto  M  et al:  Circadian variation of core body temperature in Parkinson disease patients with depression: a potential biological marker for depression in Parkinson disease.  Neuropsychobiology 2007; 56:172–179
[CrossRef] | [PubMed]
 
References Container
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References

Veazey  C;  Aki  SO;  Cook  KF  et al:  Prevalence and treatment of depression in Parkinson’s disease.  J Neuropsychiatry Clin Neurosci 2005; 17:310–323
[CrossRef] | [PubMed]
 
Weintraub  D;  Taraborelli  D;  Morales  KH  et al:  Escitalopram for major depression in Parkinson’s disease: an open-label, flexible-dosage study.  J Neuropsychiatry Clin Neurosci 2006; 18:377–383
[CrossRef] | [PubMed]
 
Lauterbach  EC;  Victoroff  J;  Coburn  KL  et al:  Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.  J Neuropsychiatry Clin Neurosci 2010; 22:8–18
[CrossRef] | [PubMed]
 
Fornaro  M;  Prestia  D;  Colicchio  S  et al:  A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation.  Curr Neuropharmacol 2010; 8:287–304
[CrossRef] | [PubMed]
 
De Berardis  D;  Di Iorio  G;  Acciavatti  T  et al:  The emerging role of melatonin agonists in the treatment of major depression: focus on agomelatine.  CNS Neurol Disord Drug Targets 2011; 10:119–132
[CrossRef] | [PubMed]
 
Martinotti  G;  Sepede  G;  Gambi  F  et al:  Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study.  J Clin Psychopharmacol 2012; 32:487–491
[CrossRef] | [PubMed]
 
Srinivasan  V;  Zakaria  R;  Othman  Z  et al:  Agomelatine in depressive disorders: its novel mechanisms of action.  J Neuropsychiatry Clin Neurosci 2012; 24:290–308
[CrossRef] | [PubMed]
 
Members of the UPDRS Development Committee:  Unified Parkinson’s Disease Rating Scale in Recent Developments in Parkinson’s Disease . Edited by Fahn  S;  Marsden  CD;  Calne  DB  et al.  Florham Park, NJ,  Macmillan Health Care Information, 1987
 
Hamilton  M:  Development of a rating scale for primary depressive illness.  Br J Soc Clin Psychol 1967; 6:278–296
[CrossRef] | [PubMed]
 
Folstein  MF;  Folstein  SE;  McHugh  PR:  “Mini-Mental State:” a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res 1975; 12:189–198
[CrossRef] | [PubMed]
 
Snaith  RP;  Hamilton  M;  Morley  S  et al:  A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale.  Br J Psychiatry 1995; 167:99–103
[CrossRef] | [PubMed]
 
European Medicines Agency European Public Assessment Report. Valdoxan, 2012; available at http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000915/human_med_001123.jsp&mid=WC0b01ac058001d124; accessed Oct 28, 2012
 
Barone  P:  Treatment of depressive symptoms in Parkinson’s disease.  Eur J Neurol 2011; 18(Suppl 1):11–15
[CrossRef] | [PubMed]
 
Meerlo  P;  Sgoifo  A;  Turek  FW:  The effects of social defeat and other stressors on the expression of circadian rhythms.  Stress 2002; 5:15–22
[CrossRef] | [PubMed]
 
O’Connor  MF;  Wellisch  DK;  Stanton  AL  et al:  Diurnal cortisol in complicated and non-complicated grief: slope differences across the day.  Psychoneuroendocrinology 2012; 37:725–728
[CrossRef] | [PubMed]
 
De Berardis D, Serroni N, Marini S, et al. Agomelatine augmentation of escitalopram therapy in treatment-resistant, obsessive-compulsive disorder: a case report. Case Rep Psychiatry 2012:642752
 
Debonnel  G;  Saint-André  E;  Hébert  C  et al:  Differential physiological effects of a low dose and high doses of venlafaxine in major depression.  Int J Neuropsychopharmacol 2007; 10:51–61
[CrossRef] | [PubMed]
 
Srinivasan  V;  De Berardis  D;  Shillcutt  SD  et al:  Role of melatonin in mood disorders and the antidepressant effects of agomelatine.  Expert Opin Investig Drugs 2012; 21:1503–1522
[CrossRef] | [PubMed]
 
Di Giannantonio  M;  Di Iorio  G;  Guglielmo  R  et al:  Major depressive disorder, anhedonia, and agomelatine: an open-label study.  J Biol Regul Homeost Agents 2011; 25:109–114
[PubMed]
 
Di Giannantonio  M;  Martinotti  G:  Anhedonia and major depression: the role of agomelatine.  Eur Neuropsychopharmacol 2012; 22(Suppl 3):S505–S510
[CrossRef] | [PubMed]
 
Adi  N;  Mash  DC;  Ali  Y  et al:  Melatonin MT1 and MT2 receptor expression in Parkinson’s disease.  Med Sci Monit 2010; 16:BR61–BR67
[PubMed]
 
Bruin  VM;  Bittencourt  LR;  Tufik  S:  Sleep–wake disturbances in Parkinson’s disease: current evidence regarding diagnostic and therapeutic decisions.  Eur Neurol 2012; 67:257–267
[CrossRef] | [PubMed]
 
Suzuki  K;  Miyamoto  T;  Miyamoto  M  et al:  Circadian variation of core body temperature in Parkinson disease patients with depression: a potential biological marker for depression in Parkinson disease.  Neuropsychobiology 2007; 56:172–179
[CrossRef] | [PubMed]
 
References Container
+
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