Antidepressants Depression Criteria Five or more of the following, nearly every day, in the same two-week span. Must include one of first two. Must cause significant distress/impairment. Cannot stem from medication, drug abuse, medical condition, or regular bereavement. • • • • • • • Depressed mood throughout most of day Diminished interest/pleasure in almost all activities Large increase/decrease in appetite Insomnia or excessive sleeping Restlessness or slowed movement Fatigue or diminished energy Feelings of worthlessness or excessive/inappropriate guilt • Difficulty thinking, concentrating, and making decisions • Recurrent thoughts about death (not just fear of dying), recurrent suicidal ideation, suicide attempt Some Forms of Depression • Unipolar Disorder – Recurring episodes of major depression • Bipolar Disorder (a.k.a. Manic-Depression) – Alternating periods of mania and depression Manic symptoms • • • • • • • • Euphoria and/or irritability Distractibility Insomnia Grandiosity Flight of ideas Increased activity Excessive speech High-risk activity Some Forms of Depression (cont) • Dysthymia – Depression with fewer or less severe symptoms, but causing persistent (2 yrs or more) dysfunction • Seasonal Affective Disorder – Depression dependent on season and/or length of day Economic costs of depresssion in US in 1990 $11.7 billion Absenteeism (26.8%) $8.3 billion Inpatient care (19.0%) $2.9 billion Outpatient care/partial care (6.6%) $12.1 billion Decreased Productive Capacity (27.7%) $7.5 billion Death from Suicide (17.1%) Andrews & Nemeroff, Am. J. Med., 1994 $1.2 billion Pharmaceutical costs (2.8%) ECT Shock (70-130 V) • delivered unilaterally • increases NE and 5-HT • 9 to 10 sessions • Side effect: memory dysfunction • generally returns fully SOME EARLY TREATMENTS Trephination: cure epileptic seizures, migraines and mental disorders Other Uses….(TMS) • • • • • • • • OCD Diabetic nerve pain Panic attacks/disorder Chronic tension headaches Social phobia Premature ejaculation Emotional problems Change in appetite and sleep patterns • Low mood • Loss of interest in people and activities • Decreased sex drive • Feelings of guilt or worthlessness • Suicidal thoughts • Difficulty concentrating • Slowed thinking • Posttraumatic stress disorder Physiological Correlates: Cortisol • 50% of depressed patients have elevated cortisol levels. • Cortisol’s primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system: and aid in fat, protein and carbohydrate metabolism • Saliva from infants of mothers with depression history has higher cortisol levels • 5-HT and other NTs indirectly affect cortisol levels • Depressed subjects frequently show early onset but reduced levels of REM sleep • Cholinergic-aminergic hypothesis suggests depressed subjects have abnormal sensitivity to ACh and amines, which regulate sleep cycles REM latency (minutes) Physiological Correlates: Sleep and REM Five age groups (years) Antidepressants • Biogenic Amine Hypothesis: deficit of NE and 5-HT function • Most antidepressants work on one or both of these systems, raising NT levels immediately • Therapeutic response requires weeks of antidepressant use • Major categories – Tricyclics – MAOIs – SSRIs – Atypicals (serotonin-norepinephrine reuptake inhibitors) • All categories have roughly equal efficacy for depression, but differ in side effects and toxicity Tricyclics • Imipramine (a TCA) accidentally found to help depression in 1960s • TCAs also have anxiolytic and analgesic action • Mechanism: Block NE and 5-HT reuptake, also blocks ACh receptors • Many anticholinergic side effects (e.g. dry mouth, blurred vision, constipation) • Can be cardiotoxic with overdose • Can impair attention, motor speed, dexterity, memory, and cause sedation Monoamine Oxidase Inhibitors • Introduced in late 1950s • Blocks MAO breakdown of monoamines, increasing NT available in terminals • Can be dangerous because MAOs also breakdown substances in the body (e.g. tyramine in aged cheese) that can be toxic at high levels • Some MAOIs are irreversible, while others temporarily inactivate MAOs • Useful in those not responding to other antidepressants, and those with many anxiety and phobic symptoms • Can have severe interactions with other drugs Selective Serotonin Reuptake Inhibitors • Used since mid-80s, especially through 1990s • Selectively inhibit reuptake of 5-HT • Few sedative and cognitive side effects? • Side effects include headache, GI discomfort, nervousness, insomnia, tremor, sweating, sexual dysfunction, but overall less severe than TCAs and MAOIs • Long term use or combination with some other drugs can lead to “serotonin syndrome” including exaggerated side effects, plus cognitive impairment and other physiological problems Zoloft (Sertraline) Prozac (Fluoxetine) Potency • Paxil is the most potent SSRI available • The reason it is effective is unclear • In a comparison with… fluoxatine(Prozac) setralin(Zoloft) paroxetine (Paxil) had significantly more withdrawal effects (The British Journal of Psychiatry (2000) 176: 363-368) The clinical implication is that adverse effects upon discontinuation is not relapse, but effects from the medication Paxil and Children • The use of paroxetine was never approved for use in the treatment of children and adolescents under 18 • Federal law does not require “off-label” studies to be available • In 2002 2.1 million prescriptions were written for children in the U.S. • Generated $55 million in sales to children Wide spread use • Used in over 100 countries as an antidepressant • Used in over 80 other countries for OCD and Panic disorder • Over 80 million patients are prescribed Paxil – 2.1 million children in USA in 2002 • After 1998, Paxil is the second most prescribed pill for anxiety disorder • Paxil is a certified treatment in over 70 countries for anxiety disorder • In 2003, Paxil is certified from FDA for social Anxiety disorder as controlled-released Tablets and cures for premenstrual dysphoric disorder (PMDD) Atypicals • Atypical refers to variation from typical TCA structure • Most popular is bupropion (a.k.a. Wellbutrin, Zyban) – a psychostimulant • Bupropion inhibits DA and NE uptake, not 5-HT • No sexual dysfunction, but can cause anxiety, restlessness, tremor, insomnia, weight loss • Also used for smoking cessation Possible Mechanisms • Increase in monoamine levels • Desensitization of autoreceptors • Reduction of stress hormones • Stimulation of neurogenesis • Placebo SSRI Withdrawal Symptoms • • • • • • • Nausea Dizziness “The Zaps” Flu-like symptoms Vertigo Depression Mania • Anxiety • Sleep problems • Gastro-intestinal problems • Sweats • Sensitivity to light and/or sound Withdrawal model ~ patients continue take to avoid withdrawal effects. Serotonin Syndrome • Resembles extreme form of SSRI overstimulation – – – – – – – – Irrational euphoria Agitation Confusion Gastronintestinal problems Fever/chills Poor coordination Muscle spasms Death • Exacerbated by MAOI’s Critiques of Antidepressants • Marketing to people who don’t need • Medicating problems • Homogenizing personalities • Pressure to use • Concealing side effects • Long-term effects