Antidepressants

Depression Criteria 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 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.

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%) $12.1 billion Decreased Productive Capacity (27.7%) $7.5 billion Death from Suicide (17.1%) $1.2 billion Pharmaceutical costs (2.8%) $2.9 billion Outpatient care/partial care (6.6%) Andrews & Nemeroff, Am. J. Med., 1994

ECT Shock ( V) delivered unilaterally increases NE and 5-HT 9 to 10 sessions Side effect: memory dysfunction generally returns fully Trephination: cure epileptic seizures, migraines and mental disorders SOME EARLY TREATMENTS

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

Physiological Correlates: Sleep and REM 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 Five age groups (years) REM latency (minutes)

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)

Potenc y 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: ) 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 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