medical model of mental illness pros and cons assumes biological etiology potentially treatable...
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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.
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
Before 1950, “Malaria therapy” Thiopental sodium – truth serum Insulin shock therapy Electroconvulsive therapy Development of Phenothiazines in
1950s
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)
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).
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
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.
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
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 anticholinergic effects 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.
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
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
clozapine continued Pharmacodynamics
High binding affinity for D4, 5-HT1C, 5-HT2, NE, 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
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
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
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
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
Potential Health Risks of Atypical Antipsychotics Weight Gain
hinders patient compliance Diabetes/Hyperglycemia Electrocardiographic Abnormalities
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.
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.
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.
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
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.
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
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
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)
Examples imipramine (Tofranil) amitriptyline (Elavil) desipramine (Norpramin)
Pharmacokinetics well absorbed with oral administration long half-lives, ~ 24 hours metabolized in liver
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 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.
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
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.
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.
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.
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.
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.
Characteristic Symptoms recurrent episodes of mania and
depression widespread cognitive deficits subtypes of varying severity (I, II,
cyclothymia) Prevalence
up to 5% of population
Treatment Issues long-term management is key Ideal treatment is to:
stabilize acute symptoms not induce alternate mood symptoms prevent future relapses
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.
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
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
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
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
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.
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%
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
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
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
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