SAUNDERS' POCKET MEDICAL FORMULARY

By JAMES THOMPSON

CONTENTS ? 1 CHEMICAL NEUROTRANSMISSION? 1 2 TRANSPORTERS RECEPTORS AND ENZYMES AS TARGETS OF PSYCHOPHARMACOLOGICAL DRUG ACTION? 29 3 ION CHANNELS AS TARGETS OF PSYCHOPHARMACOLOGICAL DRUG ACTION? 51 4 PSYCHOSIS SCHIZOPHRENIA AND THE NEUROTRANSMITTER NETWORKS DOPAMINE SEROTONIN AND GLUTAMATE? 77 5 TARGETING DOPAMINE AND SEROTONIN RECEPTORS FOR PSYCHOSIS MOOD AND BEYOND SO CALLED ANTIPSYCHOTICS ? 159 6 MOOD DISORDERS AND THE NEUROTRANSMITTER NETWORKS NOREPINEPHRINE AND AMINOBUTYRIC ACID GABA ? 244 7 TREATMENTS FOR MOOD DISORDERS SO CALLED ANTIDEPRESSANTS AND MOOD STABILIZERS ? 283 ? 8 ANXIETY TRAUMA AND TREATMENT? 359 ? 9 CHRONIC PAIN AND ITS TREATMENT? 379 10 DISORDERS OF SLEEP AND WAKEFULNESS AND THEIR TREATMENT NEUROTRANSMITTER NETWORKS FOR HISTAMINE AND OREXIN? 401 11 ATTENTION DEFICIT HYPERACTIVITY DISORDER AND ITS TREATMENT? 449 12 DEMENTIA CAUSES SYMPTOMATIC TREATMENTS AND THE NEUROTRANSMITTER NETWORK ACETYLCHOLINE? 486 CHEMICAL NEUROTRANSMISSION 1 ANATOMICAL VERSUS CHEMICAL BASIS OF NEUROTRANSMISSION? 1 GENERAL STRUCTURE OF A NEURON? 2 PRINCIPLES OF CHEMICAL NEUROTRANSMISSION? 5 NEUROTRANSMITTERS? 5 NEUROTRANSMISSION CLASSIC RETROGRADE AND VOLUME? 6 EXCITATION SECRETION COUPLING? 8 SIGNAL TRANSDUCTION CASCADES? 9 OVERVIEW? 9 FORMING A SECOND MESSENGER? 11 BEYOND THE SECOND MESSENGER TO PHOSPHOPROTEIN MESSENGERS? 13 BEYOND THE SECOND MESSENGER TO A PHOSPHOPROTEIN CASCADE TRIGGERING GENE EXPRESSION? 15 HOW NEUROTRANSMISSION TRIGGERS GENE EXPRESSION? 18 MOLECULAR MECHANISM OF GENE EXPRESSION? 18 EPIGENETICS? 23 WHAT ARE THE MOLECULAR MECHANISMS OF EPIGENETICS ? 23 HOW EPIGENETICS MAINTAINS OR CHANGES THE STATUS QUO? 24 A BRIEF WORD ABOUT RNA? 26 ALTERNATIVE SPLICING? 26 RNA INTERFERENCE? 26 SUMMARY? 28 MODERN PSYCHOPHARMACOLOGY IS LARGELY THE STORY OF CHEMICAL NEUROTRANSMISSION TO UNDERSTAND THE ACTIONS OF DRUGS ON THE BRAIN TO GRASP THE IMPACT OF DISEASES UPON THE CENTRAL NERVOUS SYSTEM AND TO INTERPRET THE BEHAVIORAL CONSEQUENCES OF PSYCHIATRIC MEDICINES ONE MUST BE FLUENT IN THE LANGUAGE AND PRINCIPLES OF CHEMICAL NEUROTRANSMISSION THE IMPORTANCE OF THIS FACT CANNOT BE OVERSTATED FOR THE STUDENT OF PSYCHOPHARMACOLOGY THIS CHAPTER FORMS THE FOUNDATION FOR THE ENTIRE BOOK AND THE ROADMAP FOR ONE S JOURNEY THROUGH ONE OF THE MOST EXCITING TOPICS IN SCIENCE TODAY NAMELY THE NEUROSCIENCE OF HOW DISORDERS AND DRUGS ACT UPON THE CENTRAL NERVOUS SYSTEM ANATOMICAL VERSUS CHEMICAL BASIS OF NEUROTRANSMISSION WHAT IS NEUROTRANSMISSION NEUROTRANSMISSION CAN BE DESCRIBED IN MANY WAYS ANATOMICALLY CHEMICALLY ELECTRICALLY THE ANATOMICAL BASIS OF NEUROTRANSMISSION IS NEURONS FIGURES 1 1 TO 1 3 AND THE CONNECTIONS BETWEEN THEM CALLED SYNAPSES FIGURE 1 4 SOMETIMES ALSO CALLED THE ANATOMICALLY ADDRESSED NERVOUS SYSTEM A COMPLEX OF HARD WIRED SYNAPTIC CONNECTIONS BETWEEN NEURONS NOT UNLIKE MILLIONS OF TELEPHONE WIRES WITHIN THOUSANDS UPON THOUSANDS OF CABLES THE ANATOMICALLY ADDRESSED BRAIN IS THUS A COMPLEX WIRING DIAGRAM FERRYING ELECTRICAL IMPULSES TO WHEREVER THE WIRE IS PLUGGED IN I E AT A SYNAPSE SYNAPSES CAN FORM ON MANY PARTS OF A NEURON NOT JUST FROM THE AXON OF ONE NEURON TO THE DENDRITE OF ANOTHER NEURON AS AXODENDRITIC SYNAPSES BUT ALSO FROM THE AXON OF ONE NEURON TO THE SOMA OF ANOTHER NEURON AS AXOSOMATIC SYNAPSES AND EVEN FROM ONE NEURON S AXON TO ANOTHER NEURON S AXON ESPECIALLY AT THE BEGINNING AND AT THE END OF THE RECEIVING NEURON S AXONS AXOAXONIC SYNAPSES FIGURE 1 2 SUCH SYNAPSES ARE SAID TO BE ASYMMETRIC SINCE COMMUNICATION IS STRUCTURALLY DESIGNED TO BE IN ONE DIRECTION I E ANTEROGRADE FROM THE AXON OF THE FIRST NEURON TO THE DENDRITE SOMA OR AXON OF THE SECOND NEURON FIGURES 1 2 AND 1 3 THIS MEANS THAT THERE ARE PRESYNAPTIC ELEMENTS THAT DIFFER FROM POSTSYNAPTIC ELEMENTS FIGURE 1 4 SPECIFICALLY A NEUROTRANSMITTER IS PACKAGED IN THE PRESYNAPTIC NERVE TERMINAL LIKE AMMUNITION IN A LOADED GUN AND THEN FIRED AT THE POSTSYNAPTIC NEURON TO TARGET ITS RECEPTORS NEURONS ARE THE CELLS OF CHEMICAL COMMUNICATION IN THE BRAIN HUMAN BRAINS ARE COMPRISED OF TENS OF BILLIONS OF NEURONS AND EACH IS LINKED TO THOUSANDS OF OTHER NEURONS THUS THE BRAIN HAS TRILLIONS OF SPECIALIZED CONNECTIONS KNOWN AS SYNAPSES NEURONS HAVE MANY SIZES LENGTHS AND SHAPES THAT DETERMINE THEIR FUNCTIONS LOCALIZATION WITHIN THE BRAIN ALSO DETERMINES FUNCTION WHEN NEURONS MALFUNCTION BEHAVIORAL SYMPTOMS MAY 1 DENDRITIC SPINES DENDRITES CELL BODY SOMA AXON PRESYNAPTIC AXON TERMINALS EN PASSANT PRESYNAPTIC AXON TERMINALS FIGURE 1 1? GENERAL STRUCTURE OF A NEURON ? THIS IS AN ARTIST S CONCEPTION OF THE GENERIC STRUCTURE OF A NEURON ALL NEURONS HAVE A CELL BODY KNOWN AS THE SOMA WHICH IS THE COMMAND CENTER OF THE NERVE AND CONTAINS THE NUCLEUS OF THE CELL ALL NEURONS ARE ALSO SET UP STRUCTURALLY TO BOTH SEND AND RECEIVE INFORMATION NEURONS SEND INFORMATION VIA AN AXON THAT FORMS PRESYNAPTIC TERMINALS AS THE AXON PASSES BY EN PASSANT OR AS THE AXON ENDS OCCUR WHEN DRUGS ALTER NEURONAL FUNCTION BEHAVIORAL SYMPTOMS MAY BE RELIEVED WORSENED OR PRODUCED GENERAL STRUCTURE OF A NEURON ALTHOUGH THIS TEXTBOOK WILL OFTEN PORTRAY NEURONS WITH A GENERIC STRUCTURE SUCH AS THAT SHOWN IN FIGURES 1 1 TO 1 3 THE TRUTH IS THAT MANY NEURONS HAVE UNIQUE STRUCTURES DEPENDING UPON WHERE IN THE BRAIN THEY ARE LOCATED AND WHAT THEIR FUNCTION IS ON THE ONE HAND ALL NEURONS HAVE A CELL BODY KNOWN AS THE SOMA AND ARE SET UP STRUCTURALLY TO RECEIVE INFORMATION FROM OTHER NEURONS THROUGH DENDRITES SOMETIMES VIA SPINES ON THE DENDRITES AND OFTEN THROUGH AN ELABORATELY BRANCHING TREE OF DENDRITES FIGURE 1 2 NEURONS ARE ALSO SET UP STRUCTURALLY TO SEND INFORMATION TO OTHER NEURONS VIA AN AXON THAT FORMS PRESYNAPTIC TERMINALS AS THE AXON PASSES BY EN PASSANT FIGURE 1 1 OR AS THE AXON ENDS PRESYNAPTIC AXON TERMINALS FIGURES 1 1 THROUGH 1 4 NEUROTRANSMISSION HAS AN ANATOMICAL INFRASTRUCTURE BUT IT IS FUNDAMENTALLY A VERY ELEGANT CHEMICAL OPERATION COMPLEMENTARY TO THE ANATOMICALLY ADDRESSED NERVOUS SYSTEM IS THUS THE CHEMICALLY ADDRESSED NERVOUS SYSTEM WHICH FORMS THE CHEMICAL BASIS OF NEUROTRANSMISSION NAMELY HOW CHEMICAL SIGNALS ARE CODED DECODED TRANSDUCED AND SENT ALONG THE WAY UNDERSTANDING THE PRINCIPLES OF CHEMICAL 2 SPINE SYNAPTIC VESICLES AXON AXODENDRITIC SYNAPSE AXOSOMATIC SYNAPSE AXOAXONIC INITIAL SEGMENT SYNAPSE AXOAXONIC TERMINAL SYNAPSE POSTSYNAPTIC DENDRITE DENDRITIC TREE DENDRITIC SPINES FIGURE 1 2? AXODENDRITIC AXOSOMATIC AND AXOAXONIC CONNECTIONS ? AFTER NEURONS MIGRATE THEY FORM SYNAPSES AS SHOWN IN THIS FIGURE SYNAPTIC CONNECTIONS CAN FORM NOT JUST BETWEEN THE AXON AND DENDRITES OF TWO NEURONS AXODENDRITIC BUT ALSO BETWEEN THE AXON AND THE SOMA AXOSOMATIC OR THE AXONS OF THE TWO NEURONS AXOAXONIC COMMUNICATION IS ANTEROGRADE FROM THE AXON OF THE FIRST NEURON TO THE DENDRITE SOMA OR AXON OF THE SECOND NEURON NEUROTRANSMISSION IS A FUNDAMENTAL REQUIREMENT FOR GRASPING HOW PSYCHOPHARMACOLOGICAL AGENTS WORK BECAUSE THESE AGENTS TARGET KEY MOLECULES INVOLVED IN NEUROTRANSMISSION DRUG TARGETING OF SPECIFIC CHEMICAL SITES THAT INFLUENCE NEUROTRANSMISSION IS DISCUSSED IN CHAPTERS 2 AND 3 UNDERSTANDING THE CHEMICALLY ADDRESSED NERVOUS SYSTEM IS ALSO A PREREQUISITE FOR BECOMING A NEUROBIOLOGICALLY INFORMED CLINICIAN THAT IS BEING ABLE TO TRANSLATE EXCITING NEW FINDINGS ON BRAIN CIRCUITRY FUNCTIONAL NEUROIMAGING AND GENETICS INTO CLINICAL PRACTICE AND POTENTIALLY IMPROVING THE MANNER IN WHICH 3