Salvatore Colicchio

A Systematic, Updated Review on the Antidepressant Agomelatine Focusing on its Melatonergic Modulation

Objective: To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine. Method: A MEDLINE, Psycinfo and Web of Science search (1966-May 2009) was performed using the following keywords: agomelatine, melatonin, S20098, efficacy, safety, adverse effect, pharmacokinetic, pharmacodynamic, major depressive disorder, bipolar disorder, Seasonal Affective Disorder (SAD), Alzheimer, ADHD, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Obsessive-Compulsive Disorder (OCD), anxiety disorders and mood disorder. Study collection and data extraction: All articles in English identified by the data sources were evaluated. Randomized, controlled clinical trials involving humans were prioritized in the review. The physiological bases of melatonergic transmission were also examined to deepen the clinical comprehension of agomelatine’ melatonergic modulation. Data synthesis: Agomelatine, a melatonergic analogue drug acting as MT1/MT2 agonist and 5-HT2C antagonist, has been reported to be an effective antidepressant therapy. Conclusions: Although a bias in properly assessing the “sleep core” of depression may still exist with current screening instruments, therefore making difficult to compare agomelatine’ efficacy to other antidepressant ones, comparative studies showed agomelatine to be an intriguing option for depression and, potentially, for other therapeutic targets as well.

Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study

Purpose The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression. Patients and methods Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale–Bipolar Version, Young Mania Rating Scale, and body mass index. Results Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group. Conclusion Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials.

Heart rate and heart rate variability modification in chronic insomnia patients.

Chronic insomnia is highly prevalent in the general population, provoking personal distress and increased risk for psychiatric and medical disorders. Autonomic hyper-arousal could be a pathogenic mechanism of chronic primary insomnia. The aim of this study was to investigate autonomic activity in patients with chronic primary insomnia by means of heart rate variability (HRV) analysis. Eighty-five consecutive patients affected by chronic primary insomnia were enrolled (38 men and 47 women; mean age: 53.2 ± 13.6). Patients were compared with a control group composed of 55 healthy participants matched for age and gender (23 men and 32 women; mean age: 54.2 ± 13.9). Patients underwent an insomnia study protocol that included subjective sleep evaluation, psychometric measures, and home-based polysomnography with evaluation of HRV in wake before sleep, in all sleep stages, and in wake after final awakening. Patients showed modifications of heart rate and HRV parameters, consistent with increased sympathetic activity, while awake before sleep and during Stage-2 non-REM sleep. No significant differences between insomniacs and controls could be detected during slow-wave sleep, REM sleep, and post-sleep wake. These results are consistent with the hypothesis that autonomic hyper-arousal is a major pathogenic mechanism in primary insomnia, and confirm that this condition is associated with an increased cardiovascular risk.

NGF serum levels variations in major depressed patients receiving duloxetine

BACKGROUNDS Nerve growth factor (NGF) is involved in the modulation of the neuro-endocrine-immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI. METHODS 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. RESULTS According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline. CONCLUSIONS A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders.

Increase in IL-6 levels among major depressive disorder patients after a 6-week treatment with duloxetine 60 mg/day: a preliminary observation.

Background: Immune modifications, including changes in interleukin (IL)-6 levels, have often been observed in major depressive disorder (MDD) during treatment with selective serotonin reuptake inhibitors (SSRIs) or the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine. Nevertheless, no equivalent observation for the SNRI duloxetine has been made to date. Method: Sixteen patients diagnosed with MDD and an actual major depressive episode according to DSM-IV criteria and 16 healthy controls entered a 6-week trial with duloxetine 60 mg/day. All subjects (n = 32) were assessed using the Hamilton Depression Rating Scale (HAM-D), the Young Mania Rating Scale (YMRS), and were monitored for IL-6 levels both at baseline and at week 6. Blood samples for IL-6 levels were evaluated by ELISA. Results: After 6 weeks of treatment, the mean total scores for HAM-D declined both in the depressed and control groups, while IL-6 modification showed an opposite trend both in depressed (12.38 ± 19.80 to 19.73 ± 18.94 pg/mL) and control subjects (12.25 ± 21.12 to 17.63 ± 20.44 pg/mL), as did YMRS (ns), although none of the subjects switched to (hypo)mania. Of note, IL-6 levels increased significantly only in the responders subgroup (n = 9; P = 0.012). Conclusion: The small sample size and weak design of this study limit the validity of our results, which should be regarded as preliminary only. Nonetheless, the trend of increasing IL-6 levels observed in responder patients treated with duloxetine should prompt further controlled, extended studies with larger samples, with the specific aim of better assessing a putative differential role of norepinephrinergic antidepressant stimulation of serotonergic reuptake inhibition in determining modifications in IL-6 levels. Ideally, more accurate replication studies may contribute to further understanding of the complex interaction of mood, antidepressant response, and the immune system.

VEGF plasma level variations in duloxetine-treated patients with major depression

BACKGROUND The vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. METHODS A total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. RESULTS According to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. LIMITATIONS Small sample size. CONCLUSIONS The opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.

Improvement of obstructive sleep apneas caused by hydrocephalus associated with Chiari malformation Type II following surgery.

Chiari malformation (CM) is the downward herniation of the caudal part of the cerebellum and/or medulla oblongata into the spinal canal. It can alter several neurological functions, including respiratory control and upper airway motility, and can be the cause of sleep-disordered breathing (SDB). The authors describe a 6-year-old boy affected by CM Type II associated with myelomeningocele who showed symptoms indicative of severe airway obstruction during sleep. Polysomnography revealed severe obstructive sleep apnea syndrome (OSAS). Magnetic resonance imaging demonstrated herniation of the cerebellar tonsils and diffuse ventricular dilation with a large pseudocystic formation in the third ventricle. Surgical marsupialization of the cystic wall was performed, associated with ventriculocystostomy and endoscopic replacement of the ventricular catheter. Polysomnography repeated 2 months after surgery revealed a striking improvement in the sleep-related respiratory pattern. The pathogenesis of OSAS was probably referable to a combination of CM and elevated intracranial pressure. However, the striking improvement of symptoms after ventriculoatrial shunt placement suggested that hydrocephalus plays a major role in this condition. Assessment and effective treatment of SDB is crucial in the care of patients with CM.

Bilateral thalamic stroke transiently reduces arousals and NREM sleep instability

The vascularization of the human thalami is supplied by many perforating arteries, which exhibit complex distribution and many possible individual variations. One rare variant is the artery of Percheron that supplies the paramedian thalami bilaterally. Its ictal occlusion may result in a symmetric paramedian infarction, which generally leads to impairment of consciousness associated with hypersomnia. Our aim is to describe in detail sleep-wake schedules, sleep structure and microstructure in a 68-year-old patient with occlusion of Percherons artery. EEG monitoring, performed 24 h after the onset of symptoms, showed severe disruption of the sleep-wake cycle, with episodes of sleep and wakefulness recurring irregularly during day and night. Thalamic nuclei are part of the human arousal system; medial thalamic nuclei play a pivotal role in sleep regulation at different levels. A diagnosis of paramedian thalamic infarction should be considered in patients who present with recurrent episodes of unresponsiveness.

Pain and the Alpha‐Sleep Anomaly: A Mechanism of Sleep Disruption in Facioscapulohumeral Muscular Dystrophy

OBJECTIVE To measure the presence of the alpha-sleep anomaly in facioscapulohumeral muscular dystrophy (FSHD) and to evaluate the association between the sleep electroencephalogram (EEG) pattern and the presence of musculoskeletal pain. DESIGN Cross-sectional study. SETTING Sleep laboratory. SUBJECTS Fifty-five consecutive adult FSHD patients, 26 women and 29 men, age 49.6 ± 15.1 years (range 18-76). INTERVENTIONS Questionnaires and polysomnography. OUTCOME MEASURES Patients were asked to indicate if in the 3 months before the sleep study they presented persisting or recurring musculoskeletal pain. Patients who reported pain were asked to fill in the Italian version of the Brief Pain Inventory and the McGill Pain questionnaire, and a 101-point visual analog scale (VAS) for pain intensity. Polysomnographic recordings were performed. EEG was analyzed by means of Fast Fourier Transform. Four power spectra bands (δ 0-4 Hz, θ 4-8 Hz, α 8-14 Hz, β 14-32 Hz) were computed. Sleep macrostructure parameters and alpha/delta EEG power ratio during non rapid eye movement (NREM) sleep were compared between patients with and without pain. RESULTS Forty-two patients in our sample reported chronic pain. VAS mean score was 55.2 ± 23.8 (range 10-100), pain rating index score was 13.8 ± 10.2, and present pain intensity was 2.5 ± 0.8. The statistical analysis documented an increased occurrence of the alpha and beta rhythms during NREM sleep in FSHD patients with pain. Significant correlations were observed between the alpha/delta power ratio during NREM sleep and pain measures. CONCLUSIONS Chronic musculoskeletal pain is frequent in FSHD patients, and it represents a major mechanism of sleep disruption.

Upper airway surgery of obstructive sleep apnea in pycnodysostosis: Case report and literature review

Pycnodysostosis is an autosomal recessive disorder due to a mutation in the cathepsin K gene, which causes a decrease of the bone turnover; a review of the literature suggests that pycnodysostosis is frequently associated with severe respiratory obstruction, which needs surgical treatment. The aim of this paper is to describe the surgical treatment of a 3½‐year‐old girl affected by Pycnodysostosis complicated by a severe sleep‐related respiratory disorder. The surgical treatment, consisting of adenotonsillectomy and palatoplasty, resulted in a striking amelioration of respiratory parameters and increased posterior airway space, and allowed the patient to avoid tracheotomy while awaiting for maxillo‐mandibular surgery.