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Psychiatric Medications Antipsychotics & Antidepressants. Psychiatric Disorders. Medical Model of Mental Illness Pros and Cons Assumes biological etiology Potentially treatable with psychotropic drugs There are no simple diagnostic tests for mental disorders.

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psychiatric disorders
Psychiatric Disorders

Medical Model of Mental Illness

  • Pros and Cons
    • Assumes biological etiology
      • Potentially treatable with psychotropic drugs
    • There are no simple diagnostic tests for mental disorders.
      • Diagnosis is based on assessment of behavioral symptoms.
classification of mental disorders
Classification of Mental Disorders
  • Anxiety Disorders
    • Generalized Anxiety Disorder, Phobic Disorder, Panic Disorder, Obsessive Compulsive Disorder, Post-traumatic Stress Disorder
  • Psychotic Disorders
    • Schizophrenia, Schizoaffective Disorder
  • Affective (Mood) Disorders
    • Dysthymia, Major (Unipolar) Depression, Bipolar Disorder
historical developments in the treatment of mental disorders
Historical Developments in the Treatment of Mental Disorders
  • Before 1950, “Malaria therapy”
  • Thiopental sodium – truth serum
  • Insulin shock therapy
  • Electroconvulsive therapy
  • Development of Phenothiazines in 1950s
antipsychotic drugs
ANTIPSYCHOTIC DRUGS
  • Historical Background
    • “Accidental” discovery of promethazine and then chlorpromazine by Henri Laborit, 1951
    • Largactil marketed in Europe, 1953
    • Thorazine marketed in U.S., 1955
  • Other Names for Antipsychotic Drugs
    • Neuroleptic
      • Literally means “clasping the neuron”
      • Refers to parkinsonian-like side effects of these drugs
    • “Major” Tranquilizers
      • Refers to sedating effects
      • Misleading terminology , chemically and pharmacologically distinct from “Minor” tranquilizers (the benzodiazepines and barbiturates)
consequences of psychiatric medications for society
Consequences of Psychiatric Medications for Society
  • Dramatic decline in numbers of people institutionalized
  • Increase in outpatient treatment programs
  • Psychiatrists roles have changed
  • From hospitals to jails or on the streets

Number of patients in nonfederal hospitals, 1946-2002 (Figure from Ksir et al., 2007).

classifying antipsychotics
Classifying Antipsychotics
  • Typical (Classical or Traditional)
    • Phenothiazines or similar to phenothiazines
    • e.g., chlorpromazine, haloperidol
  • Atypical , 2nd generation
    • e.g., clozapine, risperidone, olanzapine, quetiapine,
  • Atypical, 3rd Generation
    • e.g., aripiprazole, amisulpride, ziprasidone
phenothiazines pharmacokinetics
PHENOTHIAZINES: PHARMACOKINETICS
  • Routes of Administration/Absorption
    • Oral administration common, although absorption is erratic and unpredictable.
    • In some cases (e.g., poor compliance with oral meds), Depot injections (I.M.) may be given, once a month.
  • Distribution
    • Rapid distribution throughout the body
    • Easily cross blood brain barrier and placenta
    • Considerable protein binding in blood
    • Lower brain concentration compared to other body tissues
    • Absorbed in body fat and released slowly
  • Elimination
    • Half-life: 24-48 hours
    • Slow elimination due to protein binding and accumulation in body fat
    • Determining optimal dose, trial and error.
phenothiazines neuropharmacology
PHENOTHIAZINES: NEUROPHARMACOLOGY
  • Neuropharmacological Mechanisms
    • Block DA, NE, ACh, and histamine receptors
  • CNS actions
    • Limbic System: main therapeutic effects
    • Brain Stem: suppress behavioral arousal, antiemetic effects
    • Basal Ganglia: akathesia, dystonia, parkinsonism, and Tardive Dyskinesia
    • Hypothalamus-Pituitary: temperature regulation impaired, breast enlargement, lactation, impotence, infertility
phenothiazines side effects
PHENOTHIAZINES: SIDE EFFECTS
  • Side Effects/Toxicities
    • Sedation due to antihistamine and antiadrenergic effects
    • Postural hypotension due to antiadrenergic effects
    • dry mouth, blurred vision, constipation, urinary retention tachycardia due to anticholinergic effects
    • Extrapyramidal effects due to antidopaminergic effects in basal ganglia
    • Impaired cognition due to anticholinergiceffects
    • Despite many side effects, antipsychotics are not lethal; high therapeutic index (100 to 1000)

Tolerance/Dependence

    • Tolerance develops to some of the side effects, but there is NO evidence of tolerance to the therapeutic effects.
    • These drugs do not produce physical dependence, perhaps due to extremely slow elimination from the body.
older alternatives to phenothiazines
OLDER ALTERNATIVES TO PHENOTHIAZINES
  • haloperidol (Haldol)
    • Structurally distinct from phenothiazines
    • Similar pharmacological mechanisms and similar side effect profile
    • Effective for treating acute psychosis due to rapid onset, especially by injection
  • molindone (Moban)
    • Introduced in 1970s, structurally similar to 5-HT
    • Similar therapeutic and side effects to traditional antipsychotics
  • loxapine (Loxitane)
    • Despite structural similarity to clozapine, effects more similar to traditional antipsychotics
  • pimozide (Orap)
    • In U.S. primarily used in tx. of tics in Tourette’s Syndrome
    • Similar side effects to traditional neuroleptics, QT prolongation potentially severe
atypical antipsychotics
ATYPICAL ANTIPSYCHOTICS
  • clozapine (Clozaril)
    • Background
      • Synthesized in 1959 and introduced into clinical practice in Europe in early 1970s
      • Fatalities due to agranulocytosis delayed introduction in the U.S.
      • 1986, clinical trials in U.S.
    • Pharmacokinetics
      • p.o., absorbed well, peak plasma levels in 1-4 hours
      • variable half-life 9-30 hours
      • Blood monitoring especially important
atypical antipsychotics1
ATYPICAL ANTIPSYCHOTICS
  • clozapine continued
    • Pharmacodynamics
      • High binding affinity for D4, 5-HT1C, 5-HT2, NEa1, muscarinic and histamine receptors
      • Low D2 affinity
    • Side Effects/Toxicity
      • Sedation in about 40% of patients
      • Weight gain for up to 80% of patients
      • Constipation in about 30% of patients
      • Agranulocytosis rare
      • Withdrawal symptoms may occur upon discontinuation, alleviated by olanzapine
atypical antipsychotics2
ATYPICAL ANTIPSYCHOTICS
  • risperidone (Risperdal)
    • Introduced in 1993
    • Pharmacokinetics
      • p.o., well absorbed
      • Highly bound to plasma proteins
      • Half-life about 3 hours, active metabolite with 22 hr. half-life
    • Pharmacodynamics
      • Less effective than clozapine in relieving positive symptoms, equally effective in relieving negative symptoms
      • Better safety profile than clozapine
    • Side Effects
      • Somnolence, agitation, anxiety, headache, nausea
      • EPS at high doses (> 8 mg/day)
      • Weight gain less than with clozapine or olanzapine
atypical antipsychotics3
ATYPICAL ANTIPSYCHOTICS
  • olanzapine (Zyprexa)
    • Introduced in 1996
      • structurally/pharmacologically similar to clozapine, no agranulocytosis
    • Pharmacokinetics
      • p.o., well absorbed, peak plasma levels 5-8 hours
      • Half-life 27-38 hours
    • Pharmacodynamics
      • Superior or comparable to haloperidol
      • Comparable efficacy to clozapine
    • Side Effects
      • Weight gain
      • no agranulocytosis
      • occasional EPS
    • Other Uses of Olanzapine
      • Bipolar disorder
      • Pervasive Developmental Disorder
      • Agitation and Aggression
atypical antipsychotics4
ATYPICAL ANTIPSYCHOTICS
  • Other Atypicals
    • sertindole (Serlect)
      • 1997
      • D2/5-HT2 antagonist, no antihistaminic effects
      • Prolonged QT interval, removed from market
    • quetiapine (Seroquel)
      • 1998
      • D2/5-HT2 antagonist, similar to clozapine
      • Side effects: nausea, sedation, dizziness, weight gain no different from placebo
      • Other uses: bipolar, OCD
    • ziprasidone (Geodon)
      • D2/5-HT2 antagonist, 5-HT1A agonist
      • Relieves positive and negative symptoms, no weight gain
      • First atypical approved for IM use
      • Antidepressant activity, also effective in Bipolar disorder
      • Cardiac effects are a limiting factor, prolongs QT interval
third generation antipsychotics
“Third Generation” Antipsychotics
  • Aripiprazole
    • Pharmacodynamics
      • Considered a DA-5-HT system stabilizer
      • 5-HT2 antagonist, partial D2 and 5-HT1A agonist
    • No serious side effects
    • Other recent uses
      • Bipolar disorder, conduct disorder in children
  • Amisulpride
    • D2/D3 antagonist in limbic areas, not b.g.
    • Low doses inc. DA release, high doses block
    • First atypical that doesn’t block 5-HT receptors
atypical antipsychotics5
ATYPICAL ANTIPSYCHOTICS
  • Potential Health Risks of Atypical Antipsychotics
    • Weight Gain
      • hinders patient compliance
    • Diabetes/Hyperglycemia
    • Electrocardiographic Abnormalities
behavioral effects of antipsychotics
Behavioral Effects of Antipsychotics
  • Subjective Effects
    • In healthy subjects, classical neuroleptics produce slow and confused thinking, difficulty concentrating, clumsiness, sedation, some anxiety and irritability.
    • These effects probably responsible for poor compliance among patients prescribed these drugs.
    • Atypical antipsychotics less of a problem.
  • Performance
    • Few studies and reports are variable (deficits, improvements, no effect)
    • Studies of acute effects on cognitive performance indicate impairments are due to sedation and tolerance to these effects occur within 14 days.
laboratory studies in nonhumans
Laboratory Studies in Nonhumans
  • Unconditioned Behavior
    • Suppression of spontaneous movement with high doses causing immobility (which gave rise to the name neuroleptic)
    • Diminish frequency and intensity of aggressive behavior in most species, possibly due to decreased motor function.
  • Conditioned Behavior
    • Decrease responding on schedules maintained by positive reinforcement, although low doses may increase low response rates (rate dependency similar to amphetamine)
    • Decrease avoidance responding without affecting escape behavior, similar to CNS depressants.
laboratory studies in nonhumans1
Laboratory Studies in Nonhumans
  • Drug Discrimination
    • Some antipsychotics not easily discriminated, large doses and extended training required.
    • Generalization does not occur between Atypicals (e.g., clozapine) and Typicals (chlorpromazine) or between antipsychotics and other drug classes.
  • Self-administration
    • Antipsychotics are NOT self-administered by nonhumans.
    • They are never abused by humans.
    • In fact, compliance among patients is often a problem.
depression
DEPRESSION
  • Symptoms
    • extreme sadness/despair, diminished interest in pleasure, diminished energy, loss of appetite/weight loss, mental slowness, concentration difficulties, restless agitation, insomnia, recurrent suicidal thoughts
    • DSM-IV criteria list nine categories of symptoms with five or more symptoms present during same two week period
  • Prevalence in U.S.
    • Approx 14 million (6.6 % of adults)
    • 50% receive medical treatment, which is effective in only about 42% of those treated
depression1
Depression
  • Pathophysiology of Depression
    • A “reversible brain disease”
      • Structural, neurochemical changes in hippocampus, frontal cortex
    • Once thought to be a consequence of neurotransmitter deficiencies (e.g., NE, 5-HT)
    • More recent evidence suggests reductions in neurotrophic hormones and reduced neuronal plasticity are key factors in pathophysiology of depression.
classifying antidepressants
Classifying Antidepressants
  • First Generation (introduced in 1950s-1960s)
    • MAO Inhibitors
    • Tricyclics
  • Second Generation, Atypical (1970s-1980s)
  • SSRIs (~ 1990s)
  • SNRIs
  • Dual-Action Antidepressants
    • Combined SSRI + 5-HT2 antagonist or combined SSRI/SNRI
mao inhibitors
MAO Inhibitors
  • Examples of MAOIs
    • Iproniazid: first one introduced in 1950s, no longer on the market
    • phenelzine (Nardil)
    • tranylcypromine (Parnate)
    • moclobemide (Ludiomil): not available in U.S.
  • Pharmacokinetics
    • Short half-life, 2-4 hours
  • Neuropharmacological Actions
    • Block degradation of monoamines by MAO
    • Indirect Agonist for all Monoamines
mao inhibitors1
MAO Inhibitors
  • Side Effects
    • potentially fatal interactions with foods containing tyramine or with adrenergic drugs; hypertensive crisis.
    • MAO-A vs. MAO-B
      • Both in CNS: MAO-A mainly acts on NE and 5-HT; MAO-B mainly acts on DA.
      • MAO-A, in gastrointestinal tract; MAO-B, in liver and lungs
      • Older MAOIs acted on both types, side effects such as hypertensive crisis with tyramine rich foods.
  • Recent advances
    • Selective MAO-A inhibitor, moclobemide (not available in U.S.)
    • Transdermal delivery of selegiline (Eldapril)
tricyclic antidepressants
Tricyclic Antidepressants
  • Examples
    • imipramine (Tofranil)
    • amitriptyline (Elavil)
    • desipramine (Norpramin)
  • Pharmacokinetics
    • well absorbed with oral administration
    • long half-lives, ~ 24 hours
    • metabolized in liver
tricyclic antidepressants1
Tricyclic Antidepressants
  • Neuropharmacological Effects
    • monoamine reuptake blockade
    • Indirect agonist for all monoamines
  • Side Effects
    • Antihistaminergic effects: sedation
    • Anticholinergic effects: dry mouth, blurred vision, urinary retention, increased heart rate, cognitive impairments
    • overdose can be fatal due to cardiac toxicity, concern with suicidal patients
ssris snris
SSRIs & SNRIs
  • SSRIs
    • fluoxetine (Prozac)
    • Sertraline (Zoloft)
    • paroxetine (Paxil)
    • Fluvoxamine (Luvox)
    • citalopram (Celexa)
  • SNRIs
    • atomoxetine (Straterra)
      • Commercially available in 2003 for ADHD treatment
    • reboxetine (Edronax, Vestra)
      • Not currently available in U.S.
dual action antidepressants
Dual Action Antidepressants
  • nefazodone (Serzone)
    • 5-HT2 receptor antagonist and 5-HT/NE reuptake blocker; chronic use down regulates NE/5-HT receptors.
  • mirtazepine (Remeron)
    • Tetracyclic and NaSSA
    • 5-HT2/5-HT3 receptor antagonist; also antihistamine
  • duloxetine (Cymbalta)
    • 5-HT/NE reuptake blocker
    • also prescribed for chronic pain conditions, such as diabetic neuropathy and fibromyalgia
  • venlafaxine (Effexor)
    • 5-HT/NE reuptake blocker
    • also prescribed for general anxiety disorder
behavioral effects of antidepressants
Behavioral Effects of Antidepressants
  • Subjective Effects
    • These drugs do not produce euphoric or pleasant effects and may produce fatigue, apathy, weakness.
    • High doses may impair comprehension, cause confusion and reduce concentration.
  • Performance
    • Acute doses have detrimental effects on vigilance tasks and can cause memory and psychomotor impairments related to sedation.
    • With repeated use, these effects show tolerance.
laboratory studies in nonhumans2
Laboratory Studies in Nonhumans
  • Unconditioned Behavior
    • Antidepressants tend to increase locomotor activity in rodents
  • Conditioned Behavior
    • Increase response rates in operant assays, both low and high rates
    • Decrease avoidance responding without affecting escape behavior, similar to anxiolytic and antipsychotic drugs.
    • Do not increase, but tend to decrease punished responding.
laboratory studies in nonhumans3
Laboratory Studies in Nonhumans
  • Drug Discrimination
    • MAOIs and tricyclics are not discriminated, except at extremely high doses
    • SSRIS and SNRIs are discriminated at therapeutic doses.
  • Self-Administration
    • None of the antidepressants are self-administered by nonhumans.
health risks of antidepressants
Health Risks of Antidepressants
  • Reproduction
    • Males, delayed or impaired ejaculation
    • Males and females, Reduced sex drive and difficulties achieving orgasm.
    • Teratogenic effects with some antidepressants
      • e.g., increased risk of miscarriage with fluoxetine and TCAs.
      • e.g., Lithium in early pregnancy can cause cardiac malformations in fetus.
  • Violence/Suicide
    • Evidence for this largely from case studies.
    • Large scale studies actually show reduced incidence of suicide and violence.
health risks of antidepressants1
Health Risks of Antidepressants
  • Overdose
    • SSRIs at high doses or combined with other antidepressants or stimulants can cause Serotonin Syndrome (excess serotonin transmission)
      • Disorientation, agitation, fever, chills, diarrhea
      • If untreated, can lead to respiratory, circulatory, and kidney failure.
    • TCAS third most common cause of drug-related fatalities
      • Therapeutic index of TCAs only ~10-15.
      • SSRIs considerably safer in this regard.
bipolar disorder
Bipolar Disorder
  • Characteristic Symptoms
    • recurrent episodes of mania and depression
    • widespread cognitive deficits
    • subtypes of varying severity (I, II, cyclothymia)
  • Prevalence
    • up to 5% of population
bipolar disorder1
Bipolar Disorder
  • Treatment Issues
    • long-term management is key
    • Ideal treatment is to:
      • stabilize acute symptoms
      • not induce alternate mood symptoms
      • prevent future relapses
bipolar disorder2
Bipolar Disorder
  • Neuropathology of BD
    • Initially conceptualized as a neurochemical imbalance
    • Recent evidence of neuronal injury
      • Regional differences in neuronal density
      • Evidence of neuronal pathology in hippocampus
      • Cause or Effect?
  • Mechanisms of Drug Action
    • Recent evidence indicates antimanic drugs (e.g., lithium, valproic acid) increase levels of cellular-protective proteins and appear to reduce brain damage.
lithium
Lithium
  • History
    • 1940s, Lithium Chloride was used as salt substitute
      • severe toxicity, deaths
    • 1949, John Cade’s studies in Guinea Pigs
      • acceptance by medical community delayed
      • Lithium Carbonate
    • 1970s, clinical research demonstrated clear evidence for superior efficacy
    • Today’s “gold standard” in treating Bipolar Disorder.
    • Problems with compliance, largely due to side effects
lithium1
Lithium
  • Pharmacokinetics
    • Absorption
      • Rapid by p.o. route
      • Peak blood levels within 3 hours, complete absorption within 8 hours
      • Therapeutic efficacy directly correlated to blood levels
      • Crosses BBB slowly and incompletely
    • Elimination
      • excreted unchanged by kidneys
      • 18-24 hr. half-life
      • When initiating once daily dosing, blood levels accumulate slowly over 2 weeks until steady levels reached.
    • Determining Therapeutic Dose
      • Close blood level monitoring required
      • Recommended levels ~ 0.5-0.7 mEq/l
      • Salt intake/excretion should be constant to avoid adverse effects of Lithium
lithium2
Lithium
  • Pharmacodynamics
    • Lithium produces specific actions on mania, with no psychotropic effects in normal individuals.
    • Mechanism of action not well understood
      • second messenger signaling pathways
        • e.g., modulation of intracellular protein kinase enzymes
      • elevation of cellular protective protein, bcl-2
lithium3
Lithium
  • Side Effects and Toxicities
    • Multiple Organ Systems
      • GI: nausea, vomiting, diarrhea, abdominal pain
      • Kidneys: increased urine output, increased thirst and water intake
      • Thyroid: depressed function, becomes enlarged, weight gain
      • Skin: rashes
      • CNS: tremor, lethargy, impaired concentration and memory, dizziness, slurred speech, ataxia, muscle weakness, nystagmus
      • Cardiovascular: cardiac arrhythmia
lithium4
Lithium
  • Effects in Pregnancy
    • Teratogenic potential, particularly heart
    • Generally not advised during pregnancy, especially during first trimester.
    • If necessary tx. in a pregnant woman, discontinue use several days before delivery.
  • Problems with Compliance
    • Up to 50% of patients stop using AMA.
      • recurrent manic episodes and greatly increased suicide risk
    • Noncompliance largely due to intolerance of side effects, in particular weight gain and cognitive effects.
neuromodulators anticonvulsants
Neuromodulators/Anticonvulsants
  • Carbamazepine (Tegretol)
    • Studies in early 1990s indicated efficacy equivalent to lithium, although more recent studies show lithium to be superior.
    • Some patients resistant to both drugs respond to combination of the two.
    • Adverse effects include GI upset, sedation, ataxia, impaired vision, skin reactions, modest cognitive effects.
    • More serious risk: low white blood cell count, requires blood monitoring
    • Drug interactions due to stimulation of CYP3A4 liver enzymes
    • Teratogenic: neural tube defects in 1%
neuromodulators anticonvulsants1
Neuromodulators/Anticonvulsants
  • Valproic Acid (Depakote)
    • Introduced in 1994
    • GABA agonist
      • specific mechanisms of antimanic actions not yet determined
      • some evidence that gene expression modulated
    • Particularly effective in tx of acute mania, schizoaffective disorder, rapid cycling bd
    • Positive response in 71% of lithium-resistant pts.
    • Increased efficacy in combination with Lithium compared to either drug alone.
    • Side effects:
      • GI upset, sedation, lethargy, tremor, hair loss, cognitive impairments (in females, weight gain, polycystic ovaries, increased androgens)
    • Potential toxicities:
      • liver, pancreas, also teratogenic
neuromodulators anticonvulsants2
Neuromodulators/Anticonvulsants
  • Gabapentin (Neurontin)
    • Introduced in U.S. as anticonvulsant in 1993
    • Similar clinical efficacy to valproic acid, except gabapentin superior analgesic, valproate superior in tx of BD
    • GABA analogue, increases GABA levels in brain
    • Excellent pharmacokinetic profile: no binding to plasma proteins, not metabolized, excreted unchanged by kidneys, few pk drug interactions, half-life 5-7 hours
    • Results of clinical studies suggest this agent is most effective as adjunctive med. In pts. resistant to other more effective mood stabilizers.
    • Side effects: dizziness, dry mouth, somnolence, nausea, flatulence, reduced libido
neuromodulators anticonvulsants3
Neuromodulators/Anticonvulsants
  • Other Neuromodulators
    • Pregabalin
      • under development for tx of GAD
    • Lamotrigine
      • effective tx of acute bipolar depression, poor tx of acute manic episodes
      • Inhibits glutamate release
      • Skin rashes possible serious side effect
    • Oxcarbazine
      • Improvement on carbamazepine
    • Topiramate
      • antiepileptic, alcohol relapse prevention; key advantage weight loss
    • Tiagabine
      • limited efficacy, no controlled studies in tx of BD
    • Zonisamide
      • Mid-2000 became available in U.S., prelim. studies show promise
atypical antipsychotics for bipolar disorder
Atypical Antipsychotics for Bipolar Disorder
  • Olanzapine (Zyprexa)
    • Recent studies have shown equivalent efficacy to lithium or valproic acid
    • mid-2000 FDA approved for short-term treatment of acute mania
  • Quetiapine (Seroquel)
    • Recent studies show efficacy in treatment of Bipolar Disorder
  • Others to be investigated
    • ziprasidone
    • aripiprazole