ARRITMIA El corazón de la depresión y la ansiedad

Presentación del tema: "ARRITMIA El corazón de la depresión y la ansiedad"— Transcripción de la presentación:

1 ARRITMIA El corazón de la depresión y la ansiedad
De la bradicardia a la taquiarritmia ANDREA MARQUEZ LOPEZ MATO Instituto de Psiquiatría Biológica Integral (ipbi) 1

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3 Fisiología Del Sist. Circadiano

4 Sincronización Capacidad de los ritmos biológicos para ajustar su período endógeno con el del sincronizador Asegura la correspondencia del tiempo biológico con el tiempo geológico Sincronización mediante zeitgebers, dadores de tiempo

5 Zeitgebers Zeitstorers - Disruptor químico, físico o psicosocial
- Luz (más común y efectivo) - Temperatura - Disponibilidad de alimento - Interacciones sociales Zeitstorers - Disruptor químico, físico o psicosocial que disrupciona ritmos

6 Ritmos y Sociedad Zeitgeber social son las relaciones personales, las exigencias sociales o laborales y las tareas de entrenamiento Zeitstorers sociales son las perdidas vinculares, los cambios de horarios, los deadlines, los neonatos Swartz H, Frank E. Interpersonal and social rhythm therapy Mendlewickz J 2008 Circadian rythms and depression

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8 Ritmos Circadianos En Humanos
W S W 37.5 37.0 Core body temperature 36.5 36.0 20 Cortisol 10 3 Urine volume 2 1 5 Thyroid Stimulating Hormone 3 Some physiological functions regulated in a circadian fashion; vertical lines indicate usual sleep period. The sleep wake cycle is one of the most obvious circadian rhythms in humans. 1 25 Parathyroid Hormone 15 32 16 Motor activity 16 24 8 16 Time Modified from Czeisler and Khalsa 2000

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10 Ritmo Circadiano de la Neurogénesis
Aprendizaje Y Memoria Neurogenesis Hipocampal Neurogenesis is the proliferation and maturation of new neurons, and in adults, it occurs only in the olfactory bulb and the portion of the hippocampus called the dentate gyrus (Aimone 2010, p. 1A). Although the details are not yet fully elucidated, neurogenesis in the hippocampus appears to be important to learning and the formation of memories (Aimone 2010, p. 9A). Neurogenesis has been demonstrated in mice to change with a circadian rhythmicity. During daylight hours, when mice are not very active, there is very little detectable neurogenesis; however, during the dark hours, when mice are very active, there is a surge in neurogenesis (Holmes 2004, p. 218A). Therefore, in humans, neurogenesis may also follow a circadian rhythm. Neurogenesis 6 am 6 pm noon midnight Aimone JB et al. Trends in Cognitive Sci. 2010; Holmes MM et al. J Neurosci Res Stephen M. Stahl, MD, PhD; University of California, San Diego. 10

11 Expresión Circadiana de Receptores MT1 y 5-HT2C
Expression Levels Expression Levels Interestingly, the receptors that are bound by Valdoxan follow a circadian rhythmicity. MT1 receptors increase at the start of dark periods and stay low during light periods (Masana 2000, p. 188A). Likewise, in the hippocampus as a whole, 5-HT2C receptor expression increases in darkness and is lower in periods of light (Holmes 1997, p. 4059A). These measurements of expression level are relative and cannot be compared to each other. Masana MI et al. J Pineal Res. 2000; Holmes MC et al. J Neurosci Stephen M. Stahl, MD, PhD; University of California, San Diego. 11 11

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13 Los Ritmos Circadianos son Controlados por Genes Clock Maestros
Bmal1 y Clock son constitutivos Cuando dimerizados Bmal1 y Clock son factores transcripcionales que aumentan la expresión de varias proteinas de regulación circadiana, como Per y Cry. Per y Cry se dimerizan y fosforilan y asi actúan de represores transcripcionales de la expresión de Bmal1 y de Clock . Con el tiempo, si no se produce nuevo Per y Cry , se degradan las proteinas existentes y se levanta la represión de Bmal1 y Clock recomenzando el ciclo Bmal1 Clock Per Cry Clock genes are expressed in many cells in the body, but those in the suprachiasmatic nucleus (SCN) are considered the master circadian clock genes. These genes cycle on and off in a feedback loop to control the physiological changes seen throughout the day and night. We will discuss these genes and their proteins in more detail in the next few slides. To put it briefly, Bmal1 and Clock are constitutively expressed, and when they are bound together, they become a transcription factor that activates the expression of Per and Cry and several other circadian-regulated proteins. When they are expressed, Per and Cry dimerize, are phosphorylated, and then inhibit the expression of Bmal1 and Clock. Only after no new Per and Cry are produced and the existing proteins degrade is the transcription of Bmal1 and Clock initiated again (McClung 2007, p. 223A). Suprachiasmatic Nucleus McClung CA et al. Pharmacol & Ther Stephen M. Stahl, MD, PhD; University of California, San Diego. 13

14 Los Ritmos Circadianos son Cíclicos
Stimulate Expression Inhibit Expression Bmal1 Clock Per Cry In summary, when dimerized, Bmal1 and Clock activate the transcription of Per and Cry, which can in turn inhibit Bmal1 and Clock expression. However, because Bmal1 and Clock are necessary for Per and Cry expression, over time, they will degrade, no new protein will be produced, and the transcriptional repression will be lost. This will allow for new expression of Bmal1 and Clock, thus restarting the cyclical process of circadian pacemaker expression (McClung 2007, p. 223A). McClung CA et al. Pharmacol & Ther Stephen M. Stahl, MD, PhD; University of California, San Diego. 14

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16 Desórdenes primarios circadianos y del humor comparten algunos riesgos genéticos
The hypothesis being that circadian abnormalities may represent endophenotypes that are by definition more close to the effect of susceptibility genes. These conceptions led to investigate the role of the circadian or clock genes in depression. In the above part of the slide, circadian disorders, familial advanced sleep phase syndrome and delayed sleep phase syndrome, have been associated with depression. These disorders are associated with mutations in clock genes. This suggest that these genes may be also associated with depression. Several studies during the last years have investigated such a possibility and indeed found that circadian genes were associated with the vulnerability and the response to treatment in depression. These circadian genes regulating the biological clock it emphasizes the involvement of circadian rhythms abnormalities and depression. Courtet Eur Psychiatry 2007, Gallego & Virshup Nature Reviews Molecular Biology 2007

17 Variaciones en Ritmos Circadianos
DEPRESIÓN FASPS Alondra Normal Búho DSPS SAD MANIA????????????????

18 Biol Psych 2010, 67

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20 Ritmos Circadianos se alteran en Depresión
37.2 sanos Temperature (°C) Body 37.0 36.8 Depresivos 36.6 36.4 220 170 Cortisol (ng/ml) 120 70 20 Circadian rhythms are evident in multiple biological functions, including body temperature, hormone levels, blood pressure, metabolism, cellular regeneration, sleep-wake cycles, and DNA transcription and translation (Tardito 2010, pp. 152A, 153A; Duffield 2002, p. 556A). These biological rhythms are endogenously regulated and will continue without external stimuli. The internal coordination ordered by the circadian rhythm is essential to optimal health (Bechtold 2010, p. 191A). Physiological parameters, such as hormone production and body temperature, were measured over a 30-hour period in healthy individuals to demonstrate their circadian rhythmicity. Here we see measurements of hormones (melatonin and cortisol) and body temperature. When the same measurements were taken in patients with depression (with an average Hamilton Rating Scale for Depression (HRSD) score of 22.8), each of the parameters was altered. Body temperatures did not fluctuate to the same degree; the stress hormone cortisol was in a constantly elevated state; and melatonin levels did not increase markedly at night (Souȇtre 1989, p. 266A). 100 80 Melatonin (pg/ml) 60 40 20 6 am 6 pm noon midnight Souȇtre E et al. Psychiatry Res 20

21 Desórdenes Afectivos Ritmo Anímico en Mood score Time of day 0.4 0.2
0.0 0.6 0.8 8:15 11:15 14:15 17:15 20:15 Healthy Depressed Mood score 30 28 26 24 22 20 8 10 12 14 16 18 Time of day Low depression High depression My colleagues have well demonstrated the involvement of disrupted circadian rhythms in depression. In depressed patients, circadian rhythms appear to be flattened and disrupted, affecting several of the most debilitating symptoms of depression. The two main parameters of the core of depression that are disturbed are depressed mood and sleep-wake cycle. We know the seasonal variations of mood, seasonal variations of mood episodes, and the specificity of the seasonal affective disorder. The diurnal variation of depressed mood is considered a specifier of melancholia Recent findings have focused on the diurnal variation of positive and negative affects, the two components of mood Repeated measurements of NA and PA in daily life were obtained over 6 days from depressed outpatients and healthy individuals Positive Affect is normatively lowest in the morning, rises to a peak in the early afternoon and falls throughout the evening. In depressed patients, the positive component of mood is clearly lower in the morning and the timing of the acrophase occurs significantly later. depressed patients show lower overall levels of PA, which increases over the course of the day as in healthy controls but with a backwards shifted acrophase The same was observed in a cohort of subjects after stratification on the level of depression These findings are consistent with the circadian rhythm disturbances hypothesis of depression and could provide evidence that the mood variation in depression can be understood from the perspective of a weakened circadian function. These works provide another argument showing that the core symptom of depression, mood has also a disrupted rhythm Clinically, lower levels of the positive affect of mood in depressed patients reflect significant sadness and lethargy, a loss of interest or enjoyment in activities, and may lead to persistent anhedonia. A correlation between the severity of depression and the extent of the decrease in the positive component of mood has been also observed. I will briefly focus on some points. We know that depression is associated with rhythms as exemplified by seasonal variation of mood, seasonal variation of mood episodes, and the description of seasonal affective disorder. Diurnal variation of depressed mood have been considered as melancholic feature and predictor of response to antidepressants. Repeated measurements of NA and PA in daily life were obtained over 6 days from depressed outpatients and 39 healthy individuals Relative to healthy individuals, depressed individuals exhibited increasing PA levels during the day with a later acrophase Depression is associated with circadian rhythm alterations. These are examples of parameters for which circadian patterns have been detected. In depression, the differences between diurnal and nocturnal body temperature, and plasma melatonin and cortisol levels are blunted. But not only biological parameters are disrupted in depression. Two main parameters of the core of depression are disturbed : depressed mood and sleep-wake cycle Depressed mood is by far the most salient and characteristic symptom of depression. In addition, depressed mood follows a characteristic circadian pattern in depression: it is worse in the morning and improves throughout the day. Mood is disturbed in depressed patients compared with healthy subjects. The pattern of diurnal mood observed in healthy subjects is shifted in depressed patients and the greater the depression, the greater this mood alteration. a pattern of worse mood in the morning is mentioned in formal DSM-IV criteria for the melancholic subtype of major depression Adapted from Murray 2007

22 Severity of Phase Delay
Severidad de la Depresión correlaciona con la Severidad del Retraso de fase HAM-D Score 5 10 15 20 25 When severity of phase delay is assessed (by measuring the time from melatonin increase in response to dim light to the time of mid-sleep) and correlated with severity of depression, there is a significant increase in depression (measured by HAM-D score) with increasing severity of phase delay (Lewy 1999, p. 229A; Emens 2009, p. 260A). Severity of Phase Delay rs= – 0.61, P=0.01 Emens J et al. Psychiatry Res. 2009; Lewy AJ et al. J Biol Rhythms Stephen M. Stahl, MD, PhD; University of California, San Diego. 22

23 Depresión: Ruptura Reloj Circadiano
Cambios de fase Cambios neurogenesis Alteración temperatura Alteración melatonina Alteración cortisol Altered circadian rhythms have been associated with multiple diseases, including depression (Bechtold 2010, p. 192A). Several biological processes are controlled by circadian rhythms; these are altered when circadian rhythms are altered. Such biological processes include the phase of sleep-wake cycles, body temperature, melatonin, and cortisol (Tardito 2009, p. 152A). Depresion Bechtold DA et al. Trends in Pharmacological Sci. 2010; Tardito D et al. Medicographia Stephen M. Stahl, MD, PhD; University of California, San Diego. 23

24 EJE HPA, Ritmos Circadianos y subtipos de depresión
22 74 Total:286 45 30 115 Lopez Mato A, Beretta P, Maresca T, Congress on circadian Rhythms. ISPNE. Berlin 2010

25 EJE HPA, Ritmos Circadianos y subtipos de depresión
Hiperactividad del eje HHA con perdida del ritmo: mayor inhibición, más síntomas psicóticos, agresión y suicidio. Hipoactividad adrenal: PTSD o eventos atípicos. Ansiedad puede aumentar secreción de cortisol DST alterada en subgrupo pequeño y con depresión grave Lopez Mato A, Beretta P, Maresca T, Congress on circadian Rhythms. ISPNE. Berlin 2010

26 EJE HPA y ansiedad Psychosomatic Medicine 2010; 72

27 Depresión: Ruptura Reloj Circadiano
Cambios de fase Cambios neurogenesis Alteración temperatura Alteración melatonina Alteración cortisol Altered circadian rhythms have been associated with multiple diseases, including depression (Bechtold 2010, p. 192A). Several biological processes are controlled by circadian rhythms; these are altered when circadian rhythms are altered. Such biological processes include the phase of sleep-wake cycles, body temperature, melatonin, and cortisol (Tardito 2009, p. 152A). Depresion Bechtold DA et al. Trends in Pharmacological Sci. 2010; Tardito D et al. Medicographia Stephen M. Stahl, MD, PhD; University of California, San Diego. 27 27

28 Baja Neurogénesis y Depresión
BDNF está disminuido en depresivos.1 Volumen Hipocampal está disminuido en depresivos .2 Varios tipos de memoria están disminuidos en depresivos .3 La capacidad cognitiva depende de la función hipocampal.4 El estrés crónico o severo está asociado a la depresión y correlaciona con la disrupción de la memoria que depende del hipocampo.5 Several lines of evidence suggest that decreased neurogenesis is a characteristic of depression. Brain-derived neurotrophic factor (BDNF), a protein that increases neurogenesis, is decreased in patients with depression (Acheson 1995, p. 452A). Hippocampal volume is decreased in patients with depression (Warner-Schmidt 2006, p. 240). Patients with depression display prominent deficits in memory (Zakzanis 1998, p. 114A), and cognitive capacity depends on the function of the hippocampus (Squire 2004, p. 280A). Lastly, chronic and severe stress are well-known contributors to depression, and they correlate with disruption of hippocampus-dependent memory (Pittenger 2008, p. 89A,B). 1. Acheson A et al. Nat. 1995; 2. Warner-Schmidt JL et al. Hippocampus. 2006; 3. Zakzanis KK et al. Neuropsychiatry, Neuropsychol, and Behav Neurol. 1998; 4. Squire LR et al. Annu Rev Neurosci. 2004; 5. Pittenger C et al. Neuropscyhopharmacol 28

29 Valdoxan aumenta el BDNF en neocortex prefrontal
Es necesaria la sinergia MLT y 5 HT2 para aumentar BDNF. *p<0.001 * Valdoxan MT1 MT2 5-HT2C BDNF mRNA Levels (% Vehicle) 50 100 150 200 250 Valdoxan + Melatonin Antagonist Melatonin 5-HT2C Antagonist Vehicle Valdoxan administered to rats increased BDNF expression over vehicle in the prefrontal cortex, an area very important in the pathogenesis of depression. In the same experiment, melatonin (the natural MT1 and MT20 agonist) and S32006 (a 5-HT2C antagonist) and a melatonin receptor antagonist (S22153) coupled with Valdoxan were used as controls. As you can see here, neither of those mechanisms had a significant effect on the expression of BDNF. In addition, when Valdoxan treatment was administered with an antagonist of melatonin MT1 and MT2 receptors, the potency of Valdoxan was lost. This suggests that the unique synergy of Valdoxan is necessary to increase BDNF (Molteni 2010, p. 151A). Molteni R, Racagni G, Riva M et al. World J Biol Psychiatry Stephen M. Stahl, MD, PhD; University of California, San Diego. 29

30 Agomelatina Eficacia Antidepresiva 5HT2C r antagonismo
MT1/ MT2 Agonismo  DA  NA MT1 MT2 D2 2  Glutamate r  BDNF,  ARC  Neurogénesis Resincronización de ritmos circadianos a nivel intracelular Eficacia Antidepresiva Racagni et al, World J Biol Psy, 2011 in press

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32 ARBORETUM DE SEROTONINA

33 Disfunción Serotoninérgica en los trastornos de ansiedad: ¿tiene correlato clínico la selectividad receptorial?   5-HT1A con ansiedad generalizada (TAG) 5-HT1B/D con pánico o ansiedad neurovegetativa 5-HT1C (5-HT2C) con fobias y depresión ansiosa 5-HT1S con ansiedad somática con dolor 5-HT2A con depresión ansiosa 5-HT3 con pánico y con ansiedad psicótica 5-HT4/5-HT5 con TOC 5-HT6 con ansiedad psicótica y TOC Lopez Mato A et al. Anxia, 02

34 Perfil de alteracion circadiana GENETICA
Nueva conceptualización de los Desordenes Depresivos y de Ansiedad Perfil de alteracion circadiana GENETICA Perfil de alteracion circadiana SOCIAL SNC Eventos vitales traumáticos Medio ambiente psicosocial Enfermedad somática Alteración de ritmos circadianos Alteracion de zeitgebers y zeitstorers MT1, MT2, 5-HT2C receptors This social zeitgeber theory postulates that depressive episodes arise as a consequence of life events disturbing social zeitgebers Life events that disrupt social routines lead to changes in endogenous circadian rhythms in every individual. Whereas in most individuals such rhythms will restabilize shortly after the destabilizing events, in individuals vulnerable to mood disorders, the circadian system may not re-regulate easily thus potentially explaining a depressive episode The key structure for the organization of circadian rhythms is the suprachiasmatic nucleus, which contains high density of melatonergic MT1 /MT2 and 5HT2C receptors The central pacemaker residing in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus, regulates circadian rhythms in the brain and body of mammals. The periodicity of these endogenous rhythms is continuously synchronised or entrained by environmental signals, primarily the light–dark cycle. A major non-photic regulatory pathway for the SCN is the hormone melatonin, originating from the pineal gland. Melatonergic receptors and 5-HT2C receptors, located in the SCN are modulators of SCN function and rhythmicity. These disruptions can place substantial stress on the body's capacity to maintain stable biological rhythms, particularly sleep–wake, energy, alertness and appetite rhythms. in predisposed subjects, they may precipitate a major depressive episode Consequently, desynchronisation of internal circadian rhythms with the external world may result in mood fluctuation and contribute to a chronobiological susceptibility to depression. resetting circadian rhythms may have an antidepressant effect. To sum up, depression may be viewed as the result of the interaction between the biological clock and environmental factors, the biological clock being regulated by circadian genes potentially involved in the vulnerability to depression. The central clock is localised in the SCN, where melatonergic receptors MT1 and MT2 are highly expressed as well as the 5HT2c serotonergic receptor Circadian rhythms play a fundamental role in the regulation of human behavior and physiology Core symptoms of depression, i.e., depressed mood and sleep disturbances, follow circadian variations and are experienced by the depressed patients These three receptors, present in the biological clock, the suprachiasmatic nuclei, are known to be strongly involved in the regulation of circadian rhythms, and recent data have shown that they may act in synergy at synaptic and intracellular levels. Evidence suggests that melatonergic (MT1 and MT2) and the 5-HT2C serotonergic receptor subtypes are important modulators of circadian rhythmicity both melatonin and 5-HT are major modulators of SCN function and circadian rhythmicity Depression Hajak et al. 2009 Depresion/Ansiedad

35 EL CORAZÓN DE LA DEPRESIÓN Y LA ANSIEDAD ?
De la bradicardia a la taquiarritmia

36 MUCHAS GRACIAS Max Lerner Todos vivimos tras dos relojes
uno siendo el reloj externo que marca nuestras décadas y nos trae los cambios estacionales; El otro siendo el reloj interno, manejado por nosotros como relojeros, que determina nuestra propia cronología, nuestro propio clima y nuestra velocidad de vivir… Max Lerner Andrea Marquez Lopez Mato