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When Behaviors Won’t Change Henri Roca, MD, DAAFM, DABIHM Integrative Functional Medicine Specialist Medical Director, Greenwich Hospital Integrative Medicine Program Cardiovascular Disease and Stress Soufer, 2012 Comm; J Cardiovasc Med 2008, V9, N8 • 30-50% of patients with CAD exhibit mental-stress induced ischemia in lab testing • Often ischemia is not accompanied by angina and not explained by physical exertion • Mental stress hemodynamics are physiologically different from other cardiovascular stressors Henri Roca, MD 2-2013 drhenriroca.com Mental Ischemia Mechanisms Soufer, 2012 Comm; J Cardiovasc Med 2008, V9, N8 • Dec prefrontal cortex activity > Dec parasympathetic activity > Dec HRV and Inc TNF and Dec NO > ischemia • Inc hippocampus tone > inc cortisol and Inc NE > ischemia • Ischemia is mostly inferior and posterior • MDD is an independent risk factor for CAD and a poor prognostic indicator for CAD due to hypercortisolemia, reduced vagal tone, reduced HRV, impaired platelet function Henri Roca, MD 2-2013 drhenriroca.com Damasio – The Mental Self NATURE|VOL 423 | 15 MAY 2003 • mental self represents the individuality and continuity of a living organism. • the simplest level of self allows us to manufacture the idea that objects and events are perceived from a singular perspective, that of the organism symbolized by the self. • with the assistance of past memories of objects and events, we can piece together an autobiography and reconstruct our identity and personhood incessantly. • the body - mind as a whole is the ‘thing-process’ that is symbolized as the mental self • the brain’s representation of the structure and operations of the body is continuous Henri Roca, MD 2-2013 drhenriroca.com Damasio – Evolving the Body-Mind Self • Humoral – chemical/hormonal to hypothalamus • Neural – electrochemical • Interoceptive – viscera, muscular, vestibular • Humoral – chemical/hormonal Henri Roca, MD 2-2013 drhenriroca.com Adrenocortex Stress Profile Genova Diagnostics Henri Roca, MD 2-2013 drhenriroca.com Decompensation Henri Roca, MD 2-2013 drhenriroca.com Stage 3: Late Decompensation Henri Roca, MD 2-2013 drhenriroca.com Begin with Sympathetic Release Jorm AF MJA 2004;181:S29-S46 • Aerobic > wt training/flexibility regimens (both effective for improving mood) • Beneficial effect greater w/ increasing duration o > 20 min; maximal effect at 40 min o Lasting effects • Strong effects for mild-mod anxiety Henri Roca, MD 2-2013 drhenriroca.com Begin with Sympathetic Release Jorm AF MJA 2004;181:S29-S46 • Possible mechanism o Inc exercise correlates w/ change in brain levels of NE, DA, 5-HT o Endorphin effect o Pt playing active role in recovery sense of independence inc self-confidence inc ability to cope w/ challenging life events o Inc ANP >>direct decrease in symp activity Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com The Role of Inflammation (Arch Gen Psych, 2010 (67)12) ; Brain Behav Immune, 2011 25(2); Archives General Psych 2008 65(4) • Hypersympathetic tone with inc NE activates production of inflammatory cytokines • Relative cortisol resistance or decreased cortisol production enhances inflammation • Reduced parasympathetic tone increase • Presence of infections • Presence of autoimmune disease • Presence of Visceral Adiposity • Early Adversity > Depression leads to lifelong increase in inflammatory markers --Blocked by SSRIs or enhancing serotonin but only in those who have elevated levels of inflammation • At high levels – impaired neurogenesis, enhanced glutamatergic excitotoxicity, monoamine disruption Henri Roca, MD 2-2013 drhenriroca.com Stress and Plasticity Sleep Med Rev. 2009 June ; 13(3): 187–194; • Stress induced atrophy of dendrite spine density in hippocampus and PFC, hypertophy in amygdala • Plasticity in the adult brain especially in the hippocampus – sleep is essential • Glucocorticoids, CRF, BDNF, Inflammatory cytokines, monoamines, glutamate, CBT Henri Roca, MD 2-2013 drhenriroca.com How to Create a Sense of Personal Control and Hope JAMA, January 23/30, 2013—Vol 309, No. 4 • Conscious awareness “I • Stress induces NE can respond as I choose.” o Prunes PFC, enhances amygdala, via a-2 rec • Relaxation skills: o To let go and get focused • Excess glutamate due to decreased glial cell activity reduces PFC • Clarify deep values o “How do I want to be?” • Visualizing/experiencing o responding the new way Henri Roca, MD 2-2013 drhenriroca.com Thoughts and Behavior Wish, Thought Response From Self, History, internal cues, Expectations, desire Response From Other/Outside Influences Psychosocial Contexts Early Childhood Therapeutic Relationship Current Relationships Genetics and Epigenetics Harv Rev Psych 2011 19(3) • Genetic Gifts = Family History • Early Childhood Challenges = Epigenetic DNA Methylation o Appears to be irreversible • Later Stressful Life Events= Epigenetic histone modification • Treatments can change epigenetic modification of histones but not of DNA • For example – IL-6 and CRP were more often methylated and thus suppressed in individuals without depression compared to those with depression o Psychol Med 2011 41(5) Henri Roca, MD 2-2013 drhenriroca.com Childhood and Likelihood for Brain Resilience Brain Behav and Immune 2012, 1591 (12) • Children raised in hygiene environments o Birth to 30yo o Increased inflammation if stressed out as adults • If raised in non hygiene environment, o there is no association between stress and inflammation • Microorganisms and parasites exposure in early life leads to well modulated inflammatory system and stress system Henri Roca, MD 2-2013 drhenriroca.com Challenges to Behavior Change • Met/Met BDNF increases likelihood for decreased mood and neuroplasticity in the face of stress (Biol Psych 2005 62(5)) o Leads to rumination rather than enhanced executive functioning o Attenuated by early social support Henri Roca, MD 2-2013 drhenriroca.com Negative Bias • Negative stimuli get more attention and processing • We generally learn faster from pain than pleasure. • People work harder to avoid a loss than attain an equal gain (“endowment effect”) • Easy to create learned helplessness, hard to undo • Negative interactions: more powerful than positive • Negative experiences sift into implicit memory. Henri Roca, MD 2-2013 drhenriroca.com Negativity Bias Neuroimage 2009 47(3) • The tendency to perceive danger rather than reward signals • Associated with short allele of the serotonin transporter (5-HTT-LPR) • Worsened with early life stressors • Higher startle, higher HR, higher sympathetic tone • Activation in the brainstem, amygdala, cingulate gyrus, medial prefrontal cortex in response to fear • Influences our interpretation of the world and enhances the likelihood of triggering a stress response Henri Roca, MD 2-2013 drhenriroca.com Relaxation Techniques Jorm AF MJA 2004;181:S29-S46; Van der Watt, Current Opinion in Psychiatry 2008,21:37-42 • Meditation o One study showed sig dec in all anxiety scale scores for meditation group vs. education group • Small study, poss confounding effects of medication, lack of true placebo control o Review of multiple studies found meditation an effective intervention for high trait anxiety and GAD. • Relaxation training (progressive, release-only, cuecontrolled, differential, rapid, applied) o Review of studies found relaxation effective for dental phobia, test anxiety, panic d/o, GAD. • Breath work • Imaginal exposure: repeated/gradual exposure pt learns to cope/manage rather than eliminate stressor Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com Neural Correlates of Mindfulness Cognitive Development,22:406-430; SCAN, 2, 313-322 • Setting an intention - “top-down” ; frontal, “bottomup” limbic • Relaxing the body - parasympathetic nervous system • Feeling cared about - social engagement system • Feeling safer - inhibits amygdala/ hippocampus alarms • Encouraging positive emotion - dopamine, norepinephrine • Absorbing the benefits - positive implicit memories Henri Roca, MD 2-2013 drhenriroca.com Biofeedback • Biofeedback: measuring & relaying subject's quantifiable bodily functions e.g., BP, HR, temp, muscle activity, neurological activity, heart rate variability, sweat gland activity. • Raises pt's awareness and conscious control of unconscious physiological activities. • Allows users to gain control of physical processes previously considered an automatic response of the ANS. Henri Roca, MD 2-2013 drhenriroca.com The Inner Life of the Heart • Dually innervated. o Intrinsic – cell to cell creating a more rapid heart rate o Autonomic Nervous System via • Vagus Nerve – Parasympathetic • Sympathetic nerves and adrenal hormones • Vagus is dominant and serves to conserve cardiac reserve • Vagus creates and controls HRV Henri Roca, MD 2-2013 drhenriroca.com Heart Rate Variability (HRV) P. Rainville et al. / International Journal of Psychophysiology 61 (2006) 5– 18 • What is the relevance of HRV? - HRV reflects the autonomic nervous system (cardiac regulation). - HRV is determined non-invasively. - It is known that abnormal HRV is related to prognosis of vascular causes of death, progression of coronary atherosclerosis. Henri Roca, MD 2-2013 drhenriroca.com HRV Theory International Journal of Psychophysiology 61 (2006) 5 – 18 • Parasympathetic regulation is mediated by the vagus nerve and by acetylcholine o Rapid because the Ach is quickly degraded by acetylcholinesterase o High frequency changes in the RR interval o Further coupled with changes in respiration o The increase in intraabdominal pressure during inhaling activates the baroreceptor reflex and produces rapid increases in heart rate mediated by vagal mechanisms. o The resulting respiratory sinus arrhythmia (RSA), can be characterized by the amplitude of changes in heart rate within each respiratory cycle, and generally contributes to the high frequency components of HRV. • Sympathetic regulation is mediated by the release and relatively slow reuptake of adrenaline. • Slow changes can result from either sympathetic or parasympathetic activity. Henri Roca, MD 2-2013 drhenriroca.com 3 Domains of HRV International Journal of Psychophysiology 61 (2006) 5 – 18 • a sympathetic component; • a parasympathetic component coupled with respiration (RSA) and reactive to baroreceptor reflex activity • a parasympathetic component independent from respiration and possibly reflecting top-down neural influences on vagal output. Henri Roca, MD 2-2013 drhenriroca.com Ascending Heart Signals HeartMath Cortex: Thinking Brain Amygdala: Emotional Memory Thalamus: Synchronizes cortical activity Facilitates clear perception Inhibits clear perception Henri Roca, MD 2-2013 drhenriroca.com Health, Well-being and High Performance Requires Physiological Coherence HeartMath Cortical Inhibition (chaos) “Negative” emotions such as frustration cause chaotic heart rhythms, part of a physically harmful chain reaction leading to inhibition of the cortex. Cortical Facilitation (coherence) However, focusing on a “Positive” emotion such as appreciation creates smooth heart patterns, resulting in cortical facilitation, or coherence. Frustration Appreciation Henri Roca, MD 2-2013 drhenriroca.com Stress, Emotion and Physiological Activation HeartMath High Arousal DHEA Calm Peaceful Quiet Henri Roca, MD 2-2013 drhenriroca.com Worried Angry Resentful Cortisol Low Arousal Relaxation Acetylcholine Resignation Depressed Apathetic Low Performance Positive Emotion High Performance Excited Enthusiastic Joyful “Fight/Flight/Freeze” Adrenaline Negative Emotion Henri Roca, MD 2-2013 drhenriroca.com Acupuncture • As effective as CBT in PTSD with persistent effects at 3 mo follow up Nerv Ment Dis. 2007 Jun;195(6):504-13; J Trad Chin o JMed 2011 31(1) • May be useful in reducing symptoms of PTSD, depression, anxiety and impairment in persons w/ PTSD. o Current Opinion in Psychiatry 2008,21:37-42. • At GB 20, GV 20,24, scalp better than paroxetine o Evid Based Complement Alternat Med. 2012 Henri Roca, MD 2-2013 drhenriroca.com Acupuncture • Effective for treating headaches ….. promising treatment option for anxiety, sleep disturbances, depression and chronic pain o Syst Rev. 2012 Oct 15;1(1): • Significantly higher cure rates in pts with anxiety neuroses when treated with acupuncture and desensitization than with either treatment alone. Cure rates held at 1 yr follow-up. o MJA 2004;181:S29-S46. Henri Roca, MD 2-2013 drhenriroca.com Internal Dragons • Master Point 1 Tail Jiuwei Wild Pigeon’s o CV 14.5 (15) • ST 25 • ST 32 • ST 41 Henri Roca, MD 2-2013 drhenriroca.com Tianshu Futu Jiexi Heaven’s axis Hidden Rabbitt Release Stream Synaptic effects • • • • • • • • Neurotransmitters Neuropeptides Hormones Growth Factors Immune molecules Nutrients Toxins Infectious agents Henri Roca, MD 2-2013 drhenriroca.com Symptoms Have Multiple Neurotransmitter Etiologies Norepi Imbalance Serotonin deficiency Glutamate imbalance Depression Henri Roca, MD 2-2013 drhenriroca.com Neuroscience • Patterns are observed but must be correlated with the patient’s clinical picture • No pattern is indicative of a particular diagnosis Serotonin deficiency is correlated with major depressive disorder “A reduction in serotonin synthesis may result in depression, depression may result in a reduction in serotonin synthesis, or a third factor may be responsible for both lowering serotonin synthesis rates and triggering depression.” Henri Roca, MD 2-2013 drhenriroca.com Aan Het Rot, et al. (2009) Canadian Medical Association Journal. 180(3): 305-313. Glutamate is involved in Depression “Coverging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy.” Henri Roca, MD 2-2013 drhenriroca.com Palucha, A, et al. (2005) Drug News and Perspectives. 18(4):262. Recognize the Excitatory/Inhibitory neurotransmitters Excitatory Inhibitory Epinephrine Norepinephrine Dopamine/DOPA C Glutamate PEA Histamine Serotonin/5-HIAA Glycine Taurine GABA Henri Roca, MD 2-2013 drhenriroca.com Pathways Henri Roca, MD 2-2013 drhenriroca.com Henri Roca, MD 2-2013 drhenriroca.com Yasko, Neurological research Institute Henri Roca, MD 2-2013 drhenriroca.com COMT Val 158 >>>Met Results in low COMT activity Associated with pain, fibromyalgia, and depression Changes affect overall protein levels rather than mRNA • Helped by SAMe • • • • • • Am J Hum Genet, 2004. 75(5): p. 807-21. Pharmacogenet Genomics, 2012. 22(9): p. 673-91. Henri Roca, MD 2-2013 drhenriroca.com SAMe • As effective as tricyclics for depression, with fewer side effects. • Efficacy of 1600 mg SAMe/day po or 400 mg SAMe/day im is comparable with that of 150 mg imipramine/day po, but SAMe is better tolerated. • • • • • S-adenosylmethionine (SAMe) as treatment for depression: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed?term=16021987 Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. http://www.ncbi.nlm.nih.gov/pubmed?term=12418499 Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. http://www.ncbi.nlm.nih.gov/pubmed/19909689 A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. http://www.ncbi.nlm.nih.gov/pubmed?term=12466028 Self-help interventions for depressive disorders and depressive symptoms: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed/18710579 Henri Roca, MD 2-2013 drhenriroca.com MTHFR • • • • • C677C>>>>T Frequency is 38% of population OR Depression 1.36 OR Schizophrenia 1.44 OR Bipolar disorder 1.82 • Am J Epidemiol, 2007. 165(1): p. 1-13. Henri Roca, MD 2-2013 drhenriroca.com L Methylfolate 1. Am J Med Genetics 2008, 147B(6); 2. Popkostas Amer J Psych 2012 • Crosses the blood brain barrier (1) • Supports creation of Se, Ne, D (1) • Especially important during times of stress, high inflammation (1) • 15mg combined with SSRI effective in reducing depressive symptoms (2) o o o o o tolerable though with some gastrointestinal symptoms Esp in C677TT and in BMI >30 In SAM/SAH < 2.71 (impaired methylation) In hsCRP .2.25 In high levels of lipid peroxidation Henri Roca, MD 2-2013 drhenriroca.com MAO Int Rev Neurobiol. 2011 ; 100: 13–42.; J Neurosci. 2008 May 7; 28(19): 5099–5104. • Two isoforms – MAO A and MAO B o A primarily 5-HT, NE, D; B primarily PEA • Decrease/Block A o Increase synaptic 5HT and normetanephrine • Modulated by smoking, stress, early life stressors, aging Henri Roca, MD 2-2013 drhenriroca.com Botanicals MJA 2004;181:S29-S46 • St. John’s Wort: used in treatment of anxiety, depression, seasonal affective disorder • Inhibits reuptake of 5-HT, DA, NE, GABA and L-glutamine in vitro. • Interacts w/ CYP 3A4; may lower efficacy of other medications (warfarin, HIV medications, digoxin, anticonvulsants, OCP’s, SSRI’s, etc.). • Weak, uncontrolled evidence for efficacy of St John’s Wort for treating anxiety d/o. Henri Roca, MD 2-2013 drhenriroca.com Botanicals • • • Kava kava (Piper methysticum) – GABA ergic; D2 antagonist – Equivalent to buspirone and opipramole; metaanalysis of 9 studies shows 5 point reduction in anxiety scale (Pittler & Ernst, 2003) – Liver toxicity – CYP1A2, 2C9, 2C19, 2D6, 3A4 inhibition Valerian (Valeriana officinalis) – GABA ergic; conflicting data – in two studies equivalent to oxezapam (Dorn, 2000; Ziegler et al, 2002); equal to placebo for acute sleep problems – Rarely found as single agent – CYPA4 inhibitor (similar to grapefruit) Passion Flower (Passiflora incarnata) – onset within 7 days – Partial agonist to benzo receptors – Comparable to oxazepam – Severe nausea, vomiting, drowsine, prolongation of QTc, nonsustained ventricular tachycardia – Inhibits CYP3A4 Henri Roca, MD 2-2013 drhenriroca.com