COURSE CONTENT: PSYCHIATRIC DISORDERS: Will be approached from a neurotransmitter perspective, for example: Depression and serotonin Schizophrenia and the dopamine system MEDICAL PRACTICE Anesthesia Analgesia Hypnotics Treatment of aging disorders: Parkinson's Memory loss, including Alzheimer's Dementias of the elderly Stroke Anti-epileptics TREATMENT OF COMPULSIVE BEHAVIORS: Substance Abuse Overeating DEPRESSION: THE PHARMACOLOGY OF SEROTONIN AND NOREPI MORE ABOUT DEPRESSION: DEPRESSION A PREVALENT, AND CRIPPLING, PSYCHIATRIC DISORDER DEPRESSION IN THE USA: Lifetime incidence 11-17% Annual incidence around 15 million people Twice as likely in women Peak age at diagnosis in the mid-20s Higher in separated/divorced Lower in married than unmarried males; HIGHER in married than unmarried females Some genetic component: up to three-fold increase in likelihood if near relatives are affected Possible links to early parental death/divorce Associated with early-onset cardiovascular disease THE COST OF DEPRESSION Diagnosis carries a risk of debility/morbidity as great as angina or advanced coronary artery disease! Mortality substantially increased! a. "Self-medication" and substance abuse b. Probable cardiovascular complications c. Suicide Over 50% chance of recurrence following a single episode of major depression; goes up with repeated episodes Depression and Suicide 15% kill themselves In US, 30,000 suicides annually - most associated with depression In China, 300,000 women kill themselves annually! The "rule of sevens" One in seven depressives commit suicide 70% of suicides depressive Suicide the 7th leading cause of death in US DETECTION & TREATMENT GREATLY HANDICAPPED BY NEGATIVE PUBLIC ATTITUDES: In a recent survey: 71% agreed that mental illness due to "emotional weakness" 65% attributed to "bad parenting" 45%: Victim's fault, can will it away 43%: Mental illness incurable 35%: A consequence of "sinful behavior" 10%: Has a biological basis, involves the brain THESE ATTITUDES PREVENT DEPRESSIVES FROM SEEKING HELP MAJOR CATEGORIES OF DEPRESSION: UNIPOLAR DEPRESSION: TWO CATEGORIES: 1. Dysthymia: VERY chronic, long-term depression; DSM-IV diagnostic criteria: A. Persistently depressed mood for at least 2 YEARS B. At least 2 of the following 6: i. Appetite changes, either direction ii. Sleep problems, either direction iii. Low energy level iv. Low self-esteem v. Difficulty in concentration or decision making vi. Feelings of hopelessness 2. Major Depressive Episode: Diagnostic criteria from DSM-IV on next page MUST NOTE THAT: A. The disease is CYCLICAL, episodes are NOT permanent, but recurrence is common B. AND a single episode is PROLONGED: Usually 6 months or more Prognosis: Not good, worse with repeated episodes (see following charts) DEPRESSION AND YOU: No life is untouched by clinical depression It is a functionally crippling disease: long-term failure to realize obvious potential is almost diagnostic You know someone suffering from this disorder It is probable that neither YOU nor that SOMEONE realize they are suffering from depression THE PROBLEMS WITH ASSESSING TREATMENTS FOR DEPRESSION: Since depressive episodes come and go, ANY treatment will work! Necessitates double-blind, placebo-controlled studies! See following 2 pages THE PHARMACOLOGY OF DEPRESSION: The early 1950s saw the discovery of drug treatments for both schizophrenia and depression Chlorpromazine, a synthetic anti-histamine, was the first neuroleptic discovered The tri-cyclic antidepressants (TCAs) are chemically closely related to chlorpromazine Switzerland, 1954: Roland Kuhn is a psychiatrist at the Mnsterlingen asylum in Mnsingen Kuhn is collaborating with the drug firm Geigy in testing synthetic histamines on patients Decide to test a Geigy synthetic antihistamine (G 22355) with a side-chain identical to chlorpromazine Made schizophrenics worse! Dramatically improved depression 1957: Kuhn announces the discovery at the 2nd International Congress of Psychiatry - Zurich. There were 12 people in the audience 1958: Geigy markets the drug as imipramine Imipramine has three rings, hence tricyclic, differs from chlorpromazine by 2 atoms! THE TCAs: Like most compounds, these are dirty drugs MULTIPLE EFFECTS: these compounds variously affect norepi reuptake, serotonin reuptake, and interact with muscarinic, 1 and histaminergic receptors STRUCTURE-ACTIVITY RELATIONSHIPS: There are 10 TCAs on the US market The side-chain, NOT the three-ring structure, seems to confer pharmacological efficacy There are two major types of TCA: 3 (tertiary amine) and 2 side-chains (secondary amine): The 3 compounds generally have more activity as serotonin reuptake inhibitors, and are 10-fold more active at muscarinic, alpha noradrenergic, and histaminergic receptors + Hence have more side effects! The 2 compounds are more potent norepi reuptake blockers The 3 TCAs are: Imipramine, Amitryptyline, Clomipramine, Doxepin and Amoxapine The 2 TCAs are: Desipramine, Nortriptyline, Trimipramine, protriptyline and maprotiline Maprotiline is often called a Tetracylic