A REVIEW OF THE MAJOR ANXIETY DISORDERS: "SIMPLE" PHOBIAS Usually involve exceptional fear of things which SHOULD be avoided Common phobias include: Fear of enclosed spaces - claustrophobia Fear of heights - Acrophobia Fear of spiders - arachnophobia blood-injury phobia + Involves a "paradoxical" DROP in blood pressure at the sight of blood or injury + often accompanied by fainting + exceptionally high heritability - 2/3ds have at least one close relative with the same problem These are common disorders, with 14% of women and 8% of men having one or more simple phobias SOCIAL PHOBIAS Come in 2 varieties: Specific, especially "stage fright", fear of public speaking generalized, aka pathological shyness Unlike most anxiety disorders, no sex difference High incidence, at least 5% usually accompanied by other anxiety disorder(s) PANIC DISODER Unpredictable panic "attacks", involving some combination of: sheer, blind terror panting/shortness of breath palpitations/racing heart fear of dying, going crazy, loss of control Such attacks are typically brief (not over an hour) can occur during sleep, "nocturnal attacks" Panic attacks are often accompanied by chronic Agoraphobia Greek, "fear of the marketplace" These people are afraid of going into public and suffering a panic attack They often become home bound, unable to leave the house Sometimes involves fear of public transport, such as fear of flying Epidemiology - lifetime incidence may be as high as 4% Onset is centered in the 20s Panic disorder per se does not show major sex differences, but agoraphobia does, with severe agoraphobia almost always female GENERALIZED ANXIETY DISORDER characterized by chronic worry or anxiety about a number of events or activities sometimes called "free-floating anxiety" Sufferers live in a constant state of tension, worry and diffuse unease or apprehension Unable to relax 97% tense 86% Difficulty concentrating 86% Frightened 79% Jumpy 72% Can't control thoughts 72% Epidemiology - lifetime incidence similar to panic disorder, as high as 4% childhood onset not much sex difference BIOLOGY OF THE ANXIETY DISORDERS: PANIC DISORDER ("ATTACKS") High comorbidity with agoraphobia, depression and drug abuse As usual, twin studies suggest a substantial but as yet unidentified genetic component This disorder is accompanied by and perhaps caused by breathing disorders: Attacks are typically accompanied by breathing problems and cardiac hyperactivity Indeed, was once called "Irritable heart syndrome" Lactate infusion triggers hyperventilation and panic attacks in 50%-70% of patients with panic disorder Breathing CO2-enriched air can trigger panic attacks in 80% of patients! Even voluntary hyperventilation can trigger attacks in 30-50% of patients But unclear whether this is a cause or just an unrelated abnormality in panic victims and MOST panic attacks are not triggered by hyperventilation! The norepinephrine hypothesis: A variety of studies show that the norepi system in the locus ceruleus is activated by fear Adrenergic agonist such as yohimbine can trigger fear-like states Patients with panic disorder are hyperresponsive to yohimbine agonists can trigger panic attacks, and - blockers can reduce stage fright but not panic attacks Although recently preliminary studies of long-lasting -blockers have shown efficacy against panic attacks People with panic disorder show a very robust blunting of the normal ability of clonidine, an à2 agonist, to reduce release of growth hormone The GABA hypothesis: GABA agonists (alcohol, barbiturates, benzodiazepines) are potent anxiolytics GABA antagonists can reliably cause fear/anxiety Some studies have found abnormalities in the GABA system of sufferers of panic disorder: others have not! The serotonin hypothesis: The disorder responds well to antidepressives, including MAOI and the serotonin reuptake inhibitors The problem of panic attacks in part involves understanding the TRIGGERS which provoke and curtail the attacks These may prove to be quite different from the pronounced anxiety which accompanies such attacks GENERALIZED ANXIETY DISORDER (GAD) AND SOCIAL PHOBIA These common disorders have not received a great deal of attention from researchers Like panic disorder, all respond to benzodiazepines Fear of public speaking responds well to -blockers THE ANXIOLYTICS: MILTOWN: The first "tranquillizer" Frank Berger, Jewish refugee from Hitler, works in Britain on a muscle relaxant called Mephenesin + Notes that it has mild "tranquilizing" properties 1947: Berger immigrates to USA, goes to work for the "Carter's Little Liver Pills" people + Company chemist develops a related compound, meprobamate + Company decides there is no market for an anxiolytic!! 1949: Berger moves to Wallace labs, does full drug- development of meprobamate 1955: Wallace and Wyeth push meprobamate (Miltown or Equanil) at the annual meeting of the American Psychiatric Association Meprobamate goes ballistic, lines form in drugstores, everybody wants the "happiness" pill By 1956, one in every 20 Americans was tranquil! Mode of action is uncertain: It has sedative, anxiolytic and muscle-relaxant properties similar to the benzodiazepines, and inhibits benzodiazepine binding to the GABA receptor, but precise site is uncertain THE BENZODIAZEPINES: 1954: Hoffman-La Roche decides to develop a "psycho-sedative" drug Hoffman-La Roche a major Swiss pharmaceutical house Fearful of Nazi invasion, in 1941 Hoffman-La Roche ships its Jewish scientists, including Leo Sternbach, to its labs in Nutley, New Jersey Sternbach experiments with a family of dyes from the 1930s (the benzheptoxdiazines) with which he was familiar Nothing happens, and in 1957 Sternbach is ordered to cease and desist + While cleaning up the lab, he comes across one last untested compound + Sends it off for animal testing, with exciting results - bad monkey colony is tamed but not sedated + The drug, chlordiazepoxide (Librium) is marketed as the first benzodiazepine By the late 1960s a related compound, Valium, (also developed by Sternbach) is the most-prescribed drug in the country + by 1970, one women in 5 and one man in 13 was on "tranquilizers"!