2019 PCB Conference: Strickland Benzodiazepines (BZDs), Herbal and Alternative Treatments for Anxiety & Depression BZD Learning Objectives • List at least three uses for benzodiazepines • Discuss at least two risk factors associated with benzodiazepine prescriptions Craig Strickland, PhD, Owner Biobehavioral Education and Consultation https://sites.google.com/site/bioedcon 1 2 BZD Pharmacokinetics Clinical Uses of BZDs Generic Name Trade Name Rapidity ½ Life Dose (mg) • Treat a variety of anxiety disorders alprazolam Xanax Intermediate Short 0.75-4 • Hypnotics • Muscle relaxants chlordiaze- Librium Intermediate Long 15-100 poxide • To produce anterograde amnesia clonazepam Klonopin Intermediate Long 0.5-4 • Alcohol & other CNS depressant withdrawal • Anti-convulsant therapy diazepam Valium Rapid Long 4-40 triazolam Halcion Intermediate Very short 0.125-0.5 temazepam Restoril Short Short 7.5-30 3 4 1 2019 PCB Conference: Strickland Issues with BZDs Herbal Medication and Alternative Therapies Used in the Treatment of Depression and Anxiety • Addictive potential • Confusion between “anti-anxiety” effects and the “warm-fuzzy) • Large dose ranges • Comparison of BZDs with medications like Buspar, etc. • They work, they work well and they work quickly 5 6 Alternative Tx. Learning Objectives Background Information on herbals: Natural does not necessarily mean “safe” • List several amino acid treatments for depression • Side-effects and adverse reactions • List at least three of the most common herbal – Herbal medications are “drugs” although they treatments used to reduce the symptoms of are considered supplements by the FDA anxiety and depression – These compounds do, for the most part, • List the benefits of vagal nerve stimulation (VNS) act on the CNS for depression • Production of allergic reactions • Describe the relationship between ketamine and • Interactions with other herbs and neurogenesis/neuroplasticity with more traditional medications 7 8 2 2019 PCB Conference: Strickland Background Information on herbals: Background Information on herbals: Natural does not necessarily mean “safe” Natural does not necessarily mean “safe” •Dosing is somewhat more difficult • Because herbals are “supplements”: – % of active ingredients may differ across – Labeling is not regulated manufacturers – Herbal cannot be patented – Herbs are not “pure” • Thus, rigorous testing may or may not be – Variety of administration formulas available • Capsules (regular vs. SR vs. XR) • Data may be missing regarding: • The dried herb itself – long-term safety • Liquid extract – dose-response curves • Tincture – Drug interactions • Transdermal application 9 10 Some “safe” ways to go re: herbal products Non-Pharmaceutical • Commission E: part of the German Regulatory Authority Approaches to • The Herbal PDR Treating Depression: • Nature’s Way & other companies St. John’s Wort • Vitacost.com • Naturopaths & pharmacists • Peer-reviewed journals • Cross-referencing of sources 11 11 12 3 2019 PCB Conference: Strickland Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort • Clinical effects: mild anti-depressant – Mechanism of action: MAOI or SSRI • Inhibits reuptake of 5-HT, NE, DA • May cause down regulation of 5-HT2 autoreceptors 13 14 13 14 Herbal Treatment of Depression: Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort • Clinical effects/uses: • Other Clinical effects/uses: –Anxiety – Inflammation of the skin –Depression – Blunt injuries, wounds, burns (has –Insomnia anti-bacterial properties) –Menopausal mood changes/premenstrual – Migraine headaches syndrome • Drug interactions: –OCD – Anti-depressants (especially serotonergic) –Social anxiety disorder – Protease inhibitors – Contraceptives 15 16 15 16 4 2019 PCB Conference: Strickland Herbal Treatment of Depression: Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort •Side effects: St. John’s Wort is fairly safe •Therapeutic dose: –Agitation, anxiety, irritability, restlessness –300 mg (3x/day) –Dry mouth – Take 4-6 weeks (trial period) –Dizziness; headache •Cost: $ 4.59/60 300mg tablets (10/2015) –GI discomfort –Hypomania –Fatigue –Abnormal dreams 17 18 17 18 Herbal Treatment of Depression: Non-Pharmaceutical Ginkgo Biloba (Ginkgo) Approaches to • Not listed in the “herbal PDR” for use as Treating Depression: an anti-depressant Ginkgo Biloba • Clinical effects: mild anti-depressant – Mechanism of action is not fully known – Increase in # of 5-HT receptors • Via increase in protein synthesis • Via antioxidant mechanism (decrease in free radical activity which damages cell membranes) 20 19 20 5 2019 PCB Conference: Strickland Ginkgo and Metabotropic Herbal Treatment of Depression: Mechanism? Ginkgo Biloba (Ginkgo) •Increase in vascular flow (increases nutrients/O2 to • Increase in receptors, via increase in protein the brain) synthesis, is a metabotropic effect • Works well in persons over 50 years old (5-HT •Decrease in free radical receptors decrease with age) activity may also be such an effect 22 21 22 Ginkgo Biloba (cont.) Ginkgo Biloba (cont.) • Other indications (Commission E) – Symptomatic relief of organic brain •Side effects: generally a safe herb to use syndrome/Alzheimer’s disease – Increased bleeding time – Intermittent claudication – Mild GI complaints – Vertigo (vascular origin) – BP problems (maybe related to – Tinnitus (vascular origin) reported dizziness/headaches) • Drug interactions – Allergic skin reactions – Can take with traditional anti- – Adverse effects on oocytes depressants (unlike St. John’s Wort) – Anticoagulants/ASA (bleeding time) 24 – May interfere with anti-convulsants 23 23 24 6 2019 PCB Conference: Strickland Depression: Amino Acid Treatment Non-Pharmaceutical • Amino acids used to treat depression include Approaches to phenylalanine, tyrosine, tryptophan, and Treating Depression: methionine – Phenylalanine & tyrosine are precursors to DA Amino Acid Treatment (converts to NE) – Tryptophan (and 5-hydroxytrytophan) are precursors to serotonin (5-HT) 26 25 26 Depression: Amino Acid Treatment •Methionine gets converted to s-adenosyl-methionine Non-Pharmaceutical (SAM) Approaches to – The extract of this is SAMe (“sammy”) Treating Depression: • SAM increases levels of the monoamines Nutritional supplements • Improves monoamine binding naturally – SAM levels-lower in depressed persons – Side effects include nausea/vomiting • Dose Maximum dose of 400 mg 4x/day to be reached gradually 27 27 28 7 2019 PCB Conference: Strickland Depression: Nutritional Supplements Depression: Nutritional Supplements • Other supplements to consider: the “B” vitamins • Eicosapentaenoic acid (EPA) and docosapentaenoic including folic acid, B6 & B12 acid (DHA) : found in fish oils • Iron supplements – Enhances levels of omega-3 fatty acids – Omega-3 levels have been shown to be reduced in • Take note: people with depression – Deficiencies in the levels of these supplements can – Amount to take unclear although 3 grams/day worsen mood (3000mg) is of EPA/DHA not unusual – Thus, such supplements – Side effects: high cholesterol and increased blood • can decrease depressive symptoms sugar • but will have little effect on depressed people with normal levels of the B vitamins & iron 29 30 Polyvagal Theory, Vagal Nerve The Vagus Nerve Stimulation (VNS) and Trauma & Picture provided by Peter Jurek, MA, MS Depression http://www.peterjurek.com 31 32 8 2019 PCB Conference: Strickland Polyvagal Theory Polyvagal Theory: Dr. Stephen Porges • Cortical Control of brainstem • Brainstem regulation of the autonomic nervous system • Autonomic nervous system – Sympathetic nervous system – Parasympathetic nervous • Mammals versus reptiles and vagal evolution (and the freezing response) 33 34 Polyvagal Theory Social Engagement System • In what clinical conditions might you expect to • Changes in cardiopulmonary function see the freezing response? • Voice quality: prosody – Traumatic exposure – Intonation and tone – Depression – Stress and rhythm – Anxiety diagnoses – Vocalizations in our pets – Other? (my lovely Noelle!) • Eye contact and movement • Facial and head muscles 35 36 9 2019 PCB Conference: Strickland Polyvagal Theory in Practice: what can we do? What is vagal nerve stimulation (VNS)? • Explain the roles the different systems play • Note: this is an FDA approved technique (2005) • Educate that what their nervous systems/bodies are for refractory depression; also approved (1997) as doing is based on survival, trying to keep the person adjunctive therapy for partial-onset epilepsy safe (minimize disappointment, shame or anger • A pulse generator is surgically implanted in the about these biological responses) left chest area under the clavicle • Discuss that interpersonal interactions can change • The leads from the generator are “wrapped” nervous system function around the left vagus nerve branch; the right branch is avoided since it controls some aspects • Minimize “older” circuit activity (next slide) of cardiac function • Intermittent pulses are delivered to the nerve 37 38 How does VNS work? Other uses for VNS? • Exact anti-depressant mechanism unknown • Various anxiety disorders – Stimulation does affect blood flow in various • Alzheimer’s disease regions of the brain • Migraines – As a result, neurotransmitter activity increases, • Fibromyalgia including 5-HT and NE which would have an anti- depressant affect • Side-effects: alteration of voice quality & loudness (during pulses only), hoarseness, throat pain, dyspnea (shortness of breath) & paresthesia