Disclosures. Keys to Unlocking Psychopharmacology in Primary Care Integration. Keys to Integrated Role. Objectives. Primary Care Integration

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1 Keys to Unlocking Psychopharmacology in Primary Care Integration Disclosures Sharon Katz has no conflicts of interest or commercial support to disclose. Discussion of off-label uses will occur in this presentation, and will be identified. Sharon R. Katz, FPMH-APRN, CRNP Collaborative Psychiatric Associates, PC Abington, PA 2 Objectives Keys to Integrated Role Identify methods and tools to improve accuracy in diagnosis in primary care population Recognize impact of MTHFR and Serotonin transporter/receptor genetic deficits on brain response Define treatments for chronic pain when presenting with cooccurring depression. Identify treatment options for anxiety Define treatment options for chronic insomnia in medical population and risks Explain indication, use and dosing of L-Methylfolate, Omega 3 Fatty Acids, SAMe, and Melatonin to a patient. ACCURACY of diagnosis and medication management Scientific approach to treatment Development of treatment plan Communication of progress Evidence Based Practice Evaluation based on patient response to treatment 3 4 Primary Care Integration Integrating Assessment Develop relationship: Expectations of role, level of integration and need Trust develops with skills demonstrated Settings: Traditional Primary care offices, PCMH, OB/GYN, Rheumatology, etc. Focused areas of need: Chronic pain Drug and Alcohol Women s health History provided by Primary or specialist as guide for developing collaborative treatment plan, recent labs, ICD-10 dx. Evidence based practice scales: Getting the problem in focus and defined by symptoms PHQ-9, GAD, MDQ, YBOC, GDS, etc. Labs: CBC, Metabolic panel, Thyroid, and vitamin assays Genetic Assays: Genomind, Genesight (Assurex), Millennium, etc 5 6 Sharon Katz, FPMN APRN, CRNP 1

2 Psychometrics PHQ-9 Evidence Based Practice tools to track and trend patient progress monthly: PHQ-9 GAD-7 MDQ Adult/Child ADHD scales (ASRSv1) AIMS PANSS (Positive and Negative Symptom Scales) 9 Questions based on DSM criteria for depression Screens for severity and Suicidality Can be used in serial manner that tracks treatment effectiveness Demonstrated validity, sensitivity and specificity 88% for major depression Easy for patients to break down their symptoms and focus on specific functional effects of depression 7 8 PHQ-9 PHQ-9 Scoring 1. Little interest or pleasure in doing things 2. Feeling down, depressed or hopeless 3. Trouble falling asleep, staying asleep or sleeping too much 4. Feeling tired or little energy 5. Poor appetite or overeating 6. Feeling bad about self 7. Trouble concentrating 8. Psychomotor retardation or hyperactivity 9. Suicidal thoughts or desire to harm self 9 What treatment score indicates: 5-9 Minimal Symptoms: Support, educate, provide course of action if worse Minor Depression/Mood Dysregulation: Support, initiate psychotherapy, sleep management Major Depression Moderate: Psychotherapy, sleep and anxiety management, psychiatric evaluation and medication 20> Major Depression Severe: Evaluate effectiveness of antidepressants, increase frequency of psychotherapy, evaluate for higher level of care, involve PCP in treatment plan. 10 GAD-7 GAD-7 Developed after PHQ-9 to differentiate anxiety triggers to depression and panic 1. Feeling anxious, nervous or on edge 2. Ability to stop or control worrying 3. Multiple worries, or racing thoughts 4. Trouble relaxing 5. Restlessness 6. Becoming easily annoyed or irritated 7. Projective anxiety: Fear something awful will occur Severity of anxiety is indicated by score above : Psychotherapy, treatment plan to address concerns, monitor >15: consider psychopharmacology Assess for trauma response that might be triggering medical illness Sharon Katz, FPMN APRN, CRNP 2

3 Development of Holistic Treatment Plan Care coordination with other medical team members or specialists Psychiatric Evaluation, medication management Labs, Genetic Assays Prescription of vitamins Psychotherapy Holistic modalities: self guided goal directed activities, hobbies, mood charts Community resources Family Therapy Commonly Referred to Mental Health Team Seeking access to care for psychiatric illnesses Sleep disorders Life transitions Problems adhering to treatment recommendations Nutritional issues Co-occurring illnesses: Cardiac, GI, Endocrine, Autoimmune and Rheumatologic conditions Impact of Early Life Adversity and Addiction Assessment for PTSD in scales or interview Victimization: cycles, personality disorder, substance abuse Repeat exposure during life transitions, grief reaction, or losses. Maladaptive coping Smoking Drug Use: opiate dependency and addiction Alcohol use/abuse Marijuana use and abuse Prescription medication: hypnotics, benzodiazapams Eating disorders 15 Using Genetic Assays What does a genetic assay test? When should a genetic assay be used? Implications for Primary Care and Pain Management 16 What Does a Genetic Assay Test? Pharamcodynamics: How genes affect medication metabolism Pharamcokenetics: CYP 450 liver enzymes Drug/drug interactions prediction: inducers or inhibitor gene conditions Polymorphism due to alterations in genetic coding 17 Pharmacodynamics Genes that relate to the effect the drug has on the body, including interactions with receptors, transporters and neurotransmitters. Serotonin Transporter (SERT): SLC6A4 Serotonin Receptor: 5HT2C Dopamine Receptor: DRD2 Gated Calcium Channel Gene: CACNA1C ( L-Type voltage gaited Alpha-1C subunit) Sodium Channel Component: ANK3 (Ankyrin-G) Catechol-O-Methyltransferase (COMT) Conversion of Folic Acid to Methylfolate: MTHFR (Methylenetetrahydrofolate reductase) 18 Sharon Katz, FPMN APRN, CRNP 3

4 Pharmacokinetic Genes Cytochrome P450: 2D6, 2C19, 3A4, 2B6, 2C9 Family of hepatic enzymes which catalyze the breakdown of various substances. Variations can result in unexpected serum levels, altered efficacy and adverse events. Inhibitors: reduce the activity of CYP 450 enzyme Elevated serum levels and increased toxicity and drug to drug interactions due to reduced production of active metabolites Inducers: Can increase metabolic activity of CYP 450 enzymes. reduced serum levels decreased efficacy and/or adverse events due to increased production of toxic metabolites. Serotonin Transporter Gene: SLC64A Role: responsible for reuptake of 5HT from the synapse Impacts SSRI directly, SNRI and TCA s partially. Clinical Connection: Will indicate ability to metabolize SSRIs, predict lower stress resilience and higher rates of PTSD Long (L)/Short (S) DNA sequence polymorphism associated with a reduction in both the expression and function of serotonin transporter. Within the S sequence: A or G have different impact as well on poor metabolism. S/S: general polymorphism: More reflective of ability of the serotonin transporter gene to react to stress Serotonin Receptor 2C: 5HT2C Role: involved in regulation of satiation of food, increased metabolic syndrome due to drug metabolism. Clinical Connection: 5HT2C is blocked by atypical antipsychotics inducing metabolic effects Allele Variants: C- allele related to weight gain T- allele is a protective affect to 5HT2C enabling normal metabolism of atypical antipsychotics. Dopamine 2 Receptor: DRD2 Role: Receptor involved in movement and perception. Clinical Connection: Affinity of dopamine signaling. Most neuroleptics act through a blockade of D2 receptor to inhibit dopamine signaling. Theory: D2 responsible for all positive symptoms of psychosis, aggressive, hostile behaviors. Allele variants: DEL: reduced gene expression resulting in reduced D2 receptor density. Poor response to Atypical Antipsychotics, and increase incidence of weight gain, fatigue, decreased executive functioning, EPS. Caution with antipsychotics, use agents with lower binding affinity to D2 receptor. EPS occurs when D2 binding in high Calcium Channel: CACNA1C Role: Regulation of calcium ion signaling, mood stability, and labiality. Pore of cells remain open for prolonged periods, leading to increased excitatory signaling. Clinical Connection: Theory that variant in gene is also associated with disruptions in cognition in Schizophrenia and Bipolar disorders. Explains need for mood stabilizers. Omega 3 FA impact cell wall Sodium Channel Component: ANK3 Role: Critical protein gene linked to Sodium Channel function and firing, Hypothetically, correlates mood instability and liability to cognitive and affective changes seen in psychosis, bipolar or schizophrenia. Clinical connection: Hypothesized that variations in gene reception trigger anhedonia, perception and response to stress or threats, decreases in cognition, and reduced integrity of white matter tracts. Mood stabilizers, Omega 3 FA with EPA Sharon Katz, FPMN APRN, CRNP 4

5 COMT: Catechol-O-Methyltransferase Role: Enzyme responsible for the breakdown of dopamine and norepinephrine in the frontal lobes of brain. Clinical Connection: Critical for memory, behavioral moderation, attention span, judgment and other executive functions. Allele Variations: Val/Val: Elevated enzyme activity, increased dopamine. Dopamine stimulating medications. Met/Met: Low activity of COMT. SAMe provides co-factor to normalize enzyme activity. 25 MTHFR: Methylenetetrahydrofolate reductase Role: Enzyme responsible for the conversion of dietary folic acid to Methylfolate needed for synthesis of norepinephrine, dopamine and serotonin. Clinical connection: Enzyme needed for methylation in all cells. Augments SSRI and SNRI. Application with developmental disabilities and autoimmune disorders appears relevant (off label).. Allele variations: T allele reduces enzyme activity of MTHFR, increasing homocysteine levels. Stahl SM. L-Methylfolate: a vitamin for your monoamines. The Journal of clinical psychiatry. Sep 2008;69(9): Morrisette, DA. Psych Educational Update, NEI, February 2011 CYP Pharmacokinetic Genes Role: Most psychiatric medications are metabolized by 2D6, 2C19, 3A4, requiring dose adjustments to achieve desired results. Clinical connection: Inducers or inhibitors of CYP genes can impact ability to tolerate drugs, or create drug to drug interaction that might create critical medical consequences. Allele Variations: Metabolism ranges from Ultra rapid, normal, intermediate (also normal), and poor (double allele) Other Genetic Markers Tested CYP2B6: Liver enzyme involved in metabolism of Bupropion (Wellbutrin), Methadone, Ketamine and HIV drug Efavirenz OPRM1: Naltrexone, Morphine HLA-B: Anticonvulsants Carbamazepine, Lamotrigine, Oxcarbazepine, Phenytoin UGT2B15: Benzodiazepines Sharon Katz, FPMN APRN, CRNP 5

6 Metabolic Rates Applying Genetic Assay to Treatment Phenotype Poor Metabolizer: Low activity Intermediate Metabolizer: Partial or low normal function Extensive Metabolizer: Normal Ultra-Rapid Metabolizer: Quick activation 31 Metabolic Impact Two non-functional alleles, therefore no enzyme activity. High AE/SE One non-functional or two reduced function alleles, deceased enzyme activity 2 normal functioning alleles 2 copies of functional alleles with increased enzyme activity. Risk of increased medication clearance, low blood levels When to use Genetic Assay: History of poor response Complex Drug/Drug interactions expected: Specific Drugs: Warfarin, Carbamazepine, etc CYP inducer or inhibitor complicating AE/SE profile Genetic history unknown and failing trials of medication Known polymorphisms for genetic background 32 Classes of Genetic Assay Tests Psychiatric: Antidepressants: SSRI, SNRI, TCA Atypical and Typical Antipsychotics ADHD: Dopamine stimulants, NRIs, Alpha 2 Agonists Anxiolytics Mood Stabilizers/Anticonvulsants MTHFR Addiction: Naltrexone, Methadone Classes of Genetic Assay Testing Pain: Opiates/NSAIDs Anticoagulants/Platelet Inhibitors Complementary and Alternative supplements L-Methylfolate: 15 mg/day Omega-3 Fatty Acids (ERA): 1,000mg/day SAMe: mg/day Inositol: 2 g BID Pro/Con of Genetic Assay Pro: Complexity of medicating patients with complex needs More informed treatment the better treatment options Genetics do not change, symptoms do. Engages patients with their treatment, reinforcing why medication is needed. Directs holistic approach as well as medication Con: Pro/Con of Genetic Assay Patients put a lot of value on test, when most is general application. Cost of outside lab varies: Copay? Medicare? Medicaid? Reading of data difficult for most, including Primary Care Providers Does not indicate that patient has disease specific genes Sharon Katz, FPMN APRN, CRNP 6

7 Diagnosis and Pharmacology Common in Primary Care Addressing co-occurring Disorders: Pain, Insomnia, IBS, Migraines Anxiety, Depression, and Addictions Prescribing with Medical Comorbidity Target: Balance expression of monoamines triggered by the HPA axis and Inflammatory response Dual symptom relief Decreased pain Metabolic effects: weight, appetite, blood pressure 38 Depression in Medical Conditions SSRI/SNRI: Anti-inflammatory effect of antidepressants increases monoamines in synapses, inhibiting TNF synthesis Tricyclic Antidepressants: strong 5HT2c affect blocks H1 histaminic receptors, muscarinic cholinergic receptors, Alpha 1- adrengic receptors, and Voltage Sensitive Sodium Channels. SE have potential uses for treatment of medical co-occurring issues (migraine, IBS, insomnia, pain, weight loss, hypertension) 39 Mehl-Madrona, Future Health, Aug Anxiety/Panic Chronic Pain Program Alpha 2 Antagonist: Mirtazapine SSRI: Serotonin works to decrease anxiety, OCD as well as panic. Serotonin 1A partial agonist: Buspirone Benzodiazepines: Direct action with GABA receptors. Short and long half life to relieve acute anxiety. Alpha 2 Delta ligands: Gabapentin and Pregabalin. Chronic pain and off label for anxiety. Primary Care Integration with Mental Health PCP identifies Patient Psychological/Psychiatric Assessment Substance Abuse vs. Chronic use consequences Develop protocol and treatment agreements Drug testing: identifies metabolites of medications taken, illicit substances. Team creates treatment plan Involvement of family Sharon Katz, FPMN APRN, CRNP 7

8 Comprehensive Chronic Pain Assessment Pain and Coping: History, Current level and location, exacerbating factors, response to medications in past, goals and expectations. Collateral Information: Clinical results, family concerns, medical records Function: Affect on sleep, activity, mood, sex, etc. Substance Use History and Risk for Addiction: Current substances (including smoking, alcohol, OTC), Toxicology screening (required), history of abuse or ELA Co-occurring conditions or disorders: Depression, PTSD, cognitive impairment, medical conditions Chronic Pain: Neurobiology and Theory Target: Decrease depression, anxiety and nociceptive pathway stimulation. Chronic pain is thought to atrophy Dorsal Lateral Prefrontal Cortex due to decreased gray matter. Dorsal horn neurons of spinal cord are located entirely in CNS Opiates SNRI Alpha 2 Ligands acting at Voltage Sensitive Calcium Channels SAMHSA. (TIP) Series Pain Pain Assessment Pain: Treatment strategies Transmission: Several descending inhibitory pathways from nociceptors pass through norepinephrine and serotonergic pathways in brain. Descending noradrenergic neurons inhibit neurotransmitter release Serotonin facilitates descending pathways to spinal cord Serotonin Norepinephrine has a combined inhibitory and facilitation effect making it better for neuropathic pain control. Affective Neuroleptics Treating Medical Condition Neuroleptics inhibiting Voltage Gated Calcium Channels: Stabilizes mood Decreases anxiety Treatment for Chronic Pain Migraines Alpha 2 delta ligands (Gabapentin, Pregabalin) blocks the release of excitatory neurotransmitters, like glutamate, when excessive. Reduces nerve conduction of pain syndromes Decreases anxiety Sharon Katz, FPMN APRN, CRNP 8

9 Alpha 2 Antagonists Mental/Physical Exhaustion Alpha 2 Antagonists (Noradrenaline and specific serotonergic agents like Mirtazapine) increasing serotonin stimulation via 5-HT1 receptor. Blocks norepinephrine from turning off serotonin release. Decreases anxiety and stress reactions Increases somnolence Increases appetite, decreases nausea/vomiting Decreases IBS Decreases BP NDRI: Excitatory antidepressant Treatment of physical/mental fatigue Sexual Dysfunction Smoking cessation Bipolar Depression Attention span Holistic Based Psychiatric Nursing Treatment Decrease emotional, neurobiological, environmental stimuli: Psychotherapy to understand origin, problem solve, CBT, family therapy Alternative Techniques: EMDR, Hypnosis, Guided Imagery, Breathing Techniques, EFT, Aromatherapy Nutritional: Decrease sugars, stimulants, allergies, smaller meals and nutritional consult, vitamins, herbs Exercise Consult endocrinology Vitamin Supplementation Vitamin Supplements Vitamins B Complex Vitamins: Important nutritional supplementation for energy, DNA synthesis, depression, anxiety, memory/concentration, GI digestion, and cardiac health Vitamin D3: Deficiency linked to SAD, metabolism of Calcium and phosphorus in bones Omega 3: Important for anti-inflammatory effects, pain management, and cellular brain functioning in treating depression, bipolar illness, psychosis and ADHD. EPA > 60. Use BID dose for distribution. Doses >3,000 interferes with anticoagulation medication L-methylfolate S-Adenosyl-L-Methionine L-Methylfolate: Trimonoamine modulator Improves cognitive or mood symptoms in patients with MTHFR (methylene tetrahydrofolate) deficiency Works directly in brain to donate the methyl and Folate needed for monoamine synthesis, and DNA methylation, epigenetic regulator. Check Folate levels and/or genotying for deficient Folate synthesis prior to initiating, SAM-e: Naturally present in all cells, plays active role in cellular metabolism. Monotherapy, easily tolerated. Might induce mania or anxiety. Good for depression in Parkinson Disease. Supplemental to anti-depressant: increasing metabolism. May alter Serotonin levels in the brain and lead to serotonin syndrome when taken with tramadol. May reduce effectiveness of Levodopa, reduce blood sugar. May induce mania in Bipolar dx. Dose: 400 mg BID Max dose: 1600 mg/day SE: GI, dry mouth, headache, vertigo, insomnia, tachycardia, restlessness Sharon Katz, FPMN APRN, CRNP 9

10 Melatonin Melatonin: Natural hormone found in brain that regulates the wake sleep and anxiety associated with withdrawal. Doses: Melatonin 0.5 mg-10 mg doses Uses: Insomnia, benzodiazapams withdrawal in geriatrics, cluster headaches, anxiety, and in some cases augments cancer treatments. Side effects: Depression, raises blood pressure and blood sugar, might impact seizure control. Certain birth control pills and Luvox will increase the melatonin concentration Treating Insomnia References TCA s: Trazodone, Amitriptyline, Nortriptyline. Alam, A; Voronovich, Z & Carley, J: A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions. Primary Care Companion for CNS Disorders, published online October Risk: increases QTc, hypertension, caution with seizure. CYP 2D6 inhibitors increase TCA concentration Citrome, L; Collins, J; Nordstrom,B; Rosen, E S; Baker, R; Nadkarni, A; & Kalsekar, I Incidence of Cardiovascular Outcomes and Diabetes Mellitus Among Users of Second- Generation Antipsychotics. Journal of Clinical Psychiatry,2013: 74(12), Mood Stabilizers: Divalproic Acid or Gabapentin in PM adds stabilization Fagundes, CP, Glaser, R & Kiecolt-Glaser, J. Stressful Early Life Experiences and Immune disregulation across the lifespan. Brain, Behavior Immun. 2013, January; 27c Atypical Anti-psychotics: PM dosing for racing thoughts with Bipolar Diagnosis Ferrando, SJ, Levenson, JL, Owen, JA. Clinical manual of Psychopharmacology in the medically ill. Washington, DC: American Psychatric Publishing, Inc., 2010 Hypnotics: Note risk associated with stroke and cardiac if hypertension is uncontrolled. Benzodiazepines: Develop treatment plan minimizing short term risk Higgins, ES & George, MS. The Neuroscience of Clinical Psychiatry: The pathophysiology of behavioral illness. Philadelphia, Lippencott Williams & Watkins, Second Ed Lake, J H. and Spiegel, D: Complementary and Alternative Treatments in Mental Health Care. Washington, DC, American Psychiatric Publishing, Inc, 2007 Leussis MP, Madison JM, Petryshen TL. Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology. Biology of mood & anxiety disorders. 2012;2(1): References References Olfson,M, Kroenk, K, Wang, S & Blanco, C. Trends in Office-Based Mental Health Care Provided by Psychiatrists and Primary Care Physicians, Journal of Clinical Psychiatry, March Papakostas, G. Evidence for S-Adenosyl-l-Methionine (SAM-e) for the Treatment of Major Depressive Disorder. Journal of Clinical Psychiatry;2009; 70. Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. The Journal of clinical psychiatry. Jan 2012;73(1): Stahl SM. L-methylfolate: a vitamin for your monoamines. The Journal of clinical psychiatry. Sep 2008;69(9): Substance Abuse and Mental Health Services Administration. Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders. Treatment Improvement Protocol (TIP) Series 54. HHS Publication No. (SMA) Rockville, MD: Substance Abuse and Mental Health Services Administration, Voinov, B; Richie, WD; & Bailey,RK: Depression and Chronic Diseases: It Is Time for a Synergistic Mental Health and Primary Care Approach. Prim Care Companion CNS Disord 2013;15(2):doi: /PCC.12r0146 Yang X, Zhang B, Malony C Systematic genetic and genomic analysis of CYP 450 enzyme activities in human liver. Genomic Research. Aug 2010, 20(8): Genetic Assay references and information can be obtained from: Genomind, Inc 200 Renaissance Blvd. Suite 100 King of Prussia, PA Millennium Health Via Tazon, San Diego, CA millenniumhealth.com Assurex, Genesight Assays Sharon Katz, FPMN APRN, CRNP 10