Anxiety Disorders

Anxiety Disorders

* Panic disorder
o Can be induced by lactate or CO2 in PD sufferers (only occasionally in normal people)
o Increased activity in parahippocampal gyrus,
o Decreased activity in anterior temporal cortex & amygdala (seems odd!)
o May have 3, rather than 2, repeats of a section on chromosome 15
+ Also have joint laxity (bend too far)

* Treatments for panic disorder
o Benzodiazepines (e.g., Valium)
+ Increase frequency of Cl- channel openings in response to GABA
+ Have little or no effect alone: safer than barbiturates
+ Allopregnanolone = endogenous agonist at benzodiazepine binding site.
o Buspirone (Buspar): 5-HT1a agonist (GI/O)
o SSRIs: fluoxetine (Prozac), paroxetine (Paxil)

Benzodiazepine receptors in brain
PTSD
* Monozygotic > dizogotic concordance
o Genetics 1/3 of variance
* NMDA mechanisms in amygdala
o May mediate both the conditioning and the extinction
+ NMDA antagonists in amygdala prevent extinction
+ Hippocampus and PFC also lose effectiveness in extinction
* Not due to high levels of glucocorticoids:
o Usually PTSD sufferers have LOWER than normal cortisol levels, despite high CRH
+ Maybe it’s the high CRH that  symptoms
+ Or maybe it’s increased responsiveness to CRH or cortisol
* Individual differences in responsiveness to trauma
* Sometimes treated with β NE antagonists (propranolol) or protein synthesis inhibitors soon after the trauma or during recall of the trauma
OCD
* Increased metabolism in orbitofrontal cortex, cingulate, and caudate nuclei.
* Decreased REM latency (~ to depression)
* At least 2 gene polymorphisms:
o For BDNF, 5-HT2A receptor
* Treatment: SSRIs
Cingulotomy to treat OCD
Tourette’s Syndrome
* In many ways opposite Parkinson’s disease
* Treated with dopamine antagonists
* Monozygotic concordance: 53-77%; dizygotic concordance: 8-23%
* Witty Ticcy Ray (by Oliver Sacks): “We Touretters…are forced into levity by our Tourette’s and forced into gravity when we take Haldol….You have a natural balance: we must make the best of an artificial balance.”

THE NIGROSTRIATAL AND MESOLIMBIC DOPAMINE SYSTEMS
* Nigrostriatal and mesolimbic tracts are parallel.
o Begin in midbrain (substantia nigra & ventral tegmental area, VTA)
o End in dorsal (caudate & putamen) and ventral (N. accumbens) striatum
o Cortico-striato-pallido-thalamic-cortical loops

Nigrostriatal system
* Plans and triggers self-initiated movements
* Adjusts posture
* Degeneration  Parkinson’s disease
o Tremor at rest
o Difficulty initiating movements

Mesolimbic system
* Increases responsiveness to external and internal stimuli
* Motivation
* Motor activity
* Reward
* Drug addiction
* Schizophrenia
Nigrostriatal dopamine tract
Mesolimbic dopamine tract

Direct pathway
* Positive feedback loop
* Cortical areas that initiated the activity are further excited.
* 2 consecutive inhibitory influences
* Then an excitatory influence
* Stimulating the first inhibitory path inhibits the second inhibitory path: disinhibits the excitatory path.

Sensorimotor Cortex
Striatum
Direct pathway
* Stimulate putamen
* Inhibits GPi/SNr
via D1 receptors
Sensorimotor Cortex
Striatum
Direct Pathway
When putamen inhibits
GPi/SNr, VL/VA
is disinhibited.
Thus, VL/VA excites
sensory motor cortex.
Indirect Pathway
Negative feedback
Begins with 2
inhibitory paths:
1. Putamen to GPe
2. GPe to STN
Sensorimotor Cortex
Indirect Pathway
Those inhibitory paths disinhibit an excitatory path.
But that exc. path ends on another inhibitory path!
Function
* Direct path excites cortex; indirect path inhibits it: opposing functions.
* May “sharpen” influence on behavior
o (similar to “sharpening” receptive fields).
* May provide greater control over movement
o (similar to having both EPSPs and IPSPs on same neuron).

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

The Mesolimbic System
* Circuit is parallel to nigrostriatal system:
o Direct and indirect pathways
o Prefrontal cortex vs. sensory motor
o N. accumbens (ventral striatum), vs. caudate & putamen (dorsal striatum)
o Ventral pallidum vs. GPi and GPe
o Mediodorsal thalamus vs. VL/VA
Prefrontal Cortex
VP normally inhibits

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

Glutamate/DA balance in schizophrenia
* Cortical or hippocampal hypofunction may  decrease glutamate in NAcc and striatum
* decrease tonic DA release
* increase DA receptor sensitivity
* hyperresponsive to phasic input

Anxiety Disorders.ppt

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Movement Disorders

Movement Disorders

* Background
o AKA Extrapyramidal Disorders
o These disorders impair the regulation of voluntary motor activity w/o affecting the strength, sensation, or cerebellar fcn.
o Result from dysfunction of the basal ganglia
+ Caudate
+ Putamen
+ Globus Pallidus
+ Subthalamic Nucleus
+ Substantia Nigra
+ Lentiform Nucleus
# Putamen & Globus Pallidus
+ Corpus Striatum
# Lentiform Nucleus + Caudate Nucleus
* Basal Ganglia Circuitry (Fig 7-1)
o Corticocortical Loop:
Cerebral Cortex
Caudate & Putamen
Internal Segment
Globus Pallidus
Thalamus
* Basal Ganglia Circuitry (Fig 7-1)
o Nigrostriatal Loop:
Substantia Nigra
Caudate & Putamen
* Basal Ganglia Circuitry (Fig 7-1)
o Striatalpallidal Loop:
Caudate & Putamen
External Segment
Globus Pallidus
Subthalamic Nuclei
Internal Segment
Globus Pallidus
* Types of Abnormal Movements
o Tremor: rhythmic movement characterized by when it occurs
+ Postural Tremor
# During sustained posture
+ Intention Tremor
# During movement; absent at rest
+ Resting Tremor
# At rest
o Chorea: irregular muscle jerks
+ Florid Cases
# Fully developed
# Forceful movements of limbs, head, facial grimacing, & tongue movements
+ Mild Cases
# Characterized by:
* Clumsiness
* Milkmaid grasp
* Absent in sleep
o Hemiballismus
+ Unilateral Chorea
+ Involves the proximal muscles
+ Vascular disease of contralateral subthalamic nucleus
o Athetosis
+ Continued slow, sinuous, & writhing movements
o Dystonia: sustained athetotic movements
+ Segmental Dystonia
# Affects one or more limbs
+ Focal Dystonia
# Affects localized muscle groups
+ Palliative/Provocative
+ Causes
o Myoclonus
+ Definition
+ Classification
+ Generalized: widespread
# Physiological
# Essential
# Epileptic
# Symptomatic
+ Segmental: more localized
o Tics
+ Definition
+ Palliative/Provocative
+ Types
# Transient Simple: common in children, resolve w/I 1 yr
# Chronic: any age, no tx
# Persistent Simple or Multiple: onset before 15 yoa, resolve in adults
# Chronic Multiple: Tourette’s Sydrome
* Hypokinetic Movement Disorders
o Parkinson’s Disease
* Hyperkinetic Movement Disorders
o Huntington’s Disease
o Wilson’s Disease
o Tourette’s Syndrome
o Restless Leg Syndrome
* Parkinson’s Disease - Hypokinetic
o Defined as a syndrome consisting of variable combination of tremor, rigidity, bradykinesia, and characteristic disturbance of gait and posture
o Onset: mid-late life; mean age is 57 yrs
o Epidemiology:
+ Affects all ethnicities
+ has equal M/F distribution
+ occurs 1-2 per 1,000 people in general population
+ occurs 1 per 100 people that are over 65 yrs
+ 4th most common disease in the elderly
* Parkinson’s Disease - Hypokinetic
o Cause: unknown
o Pathophysiology:
+ Loss of dopaminergic cells in the substantia nigra
# Dopamine’s normal function
+ Over excitation of the caudate & putamen
+ Over excitation of the corticospinal tracts
+ Oscilation of feedback
+ Decrease in thalamic excitation of the motor cortex
o Four Hallmark Signs
+ Resting Tremor (Pill-Rolling)
+ Rigidity (Lead-Pipe or Cogwheel)
+ Bradykinesia
+ Flexed Posture with shuffling gait (Festinating)
o Examination:
+ History
+ Phsyical Findings:
# Passive movement
# Muscle Strength
# Sensory
# Deep Tendon Reflexes
# Autonomic
# Myerson’s Sign
# Pull Test
o Diagnosis:
+ Four Hallmark signs
+ Tremor is absent in 30% of patients
o Differential Diagnosis
+ Involuntary tremor vs. Intentional tremor
+ Depression
+ Wilson’s Disease
+ Huntington’s Disease
o A neurodegenerative disorder which predominately has behavioral, cognitive, or signs
o Onset: Usually begins during adult life
o Epidemiology:
+ 5-10 per 100,000 in the US
+ 50% chance to pass on the disorder
+ Anticipation
+ Paternal Descent
* Huntington’s Disease – Hyperkinetic
o Cause: Autosomal Dominant Disorder
o Pathophysiology:
+ Mutation on chromosome 4: CAG repeats
+ CAG Normal Function: codes for glutamine
+ Over-expression of the gene: i.e. excess glutamine
+ Uncertainty?
* Huntington’s Disease – Hyperkinetic
o Cause: Autosomal Dominant Disorder
o Pathophysiology:
+ Pathological Changes
# Atrophy & neuronal degeneration of cortex
# Hallmark: caudate atrophy
+ Projected Conclusion?
# Over activity
# Under activity
o Examination:
+ Physical Findings
# Initial Findings
* Gradual onset
* Slowed saccadic movements 1st sign
* In 85% chorea is predominate movement disorder
# Juvenile Form
* AKA The Westphal Variant
* Rigidity & bradykinesia
* Tremors, Dystonic postures, & Ataxia
* Mental retardation, Seizures, & myoclonus
o Examination:
+ Physical Findings
# Adult Onset
* Prominent chorea
* Bradykinesia
* Postural reflex compromise
# Terminal Phase
* Dysarthria, dysphagia, & respiratory difficulties
# General
* Cognitive impairment
* Depression
* Psychiatric disorders
* Wilson’s Disease – Hyperkinetic
o Onset
+ Hepatic Dysfunction – 11 yoa
+ Neurological Dysfunction – 19 yoa
o Epidemiology
+ Rare
+ 1 in 40,000 people
o Cause: Autosomal Recessive Disorder
o Pathophysiology
+ Abnormal copper metabolism
+ Deposition of copper in tissues
o Examination
+ Physical Findings
# Children: hepatic dysfunction predominates
* Sardonic Smile
* Behavioral problems
# Adults: neurological dysfunction predominates
* Parkinsonian features
# General
* Hallmark: Kayser-Fleischer Rings
* 1/3 experience psychiatric symptoms
* Other ocular abnormalities
* Gilles de la Tourette Syndrome – Hyperkinetic
o Diagnosed when childhood onset tics are multifocal, motor or vocal, lasting longer than 1 yr and naturally wax and wane
o Cause: unknown
o Onset: 2-21 yoa
o Male predilection
* Gilles de la Tourette Syndrome – Hyperkinetic
o Examination
+ Physical Findings
# Simple Tics
* Motor: blinking, facial grimacing, shoulder shrugging
* Vocal: throat clearing, grunting, snorting, barking
# Complex Tics
* Motor: hopping, skipping, Echopraxia
* Vocal: Coprolalia, Echolalia, Palilalia
* Restless Legs Syndrome – Hyperkinetic
o Common movement disorder
o Diagnostic Criteria
# Desire to move limbs which is associated with unpleasant sensations
# Restlessness
# Worsening of symptoms @ rest w/ temporary relief w/ movement
# Worsening of symptoms @ night
* Restless Legs Syndrome – Hyperkinetic
o Common Descriptions
+ Always unpleasant, but not necessarily painful
+ Need to move
+ Crawling
+ Tingling
+ Itching
+ Restless

Movement Disorders.ppt

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Placebo Control: What is it? Why do we use it? Is it ethical?

Placebo Control: What is it? Why do we use it? Is it ethical?
By:Tom Talbot, MD MPH
Vanderbilt School of Medicine

Placebo
* Placebo = “I shall please”
* Pharmocologically inert substances used to satisfy patients that something being done for them (“please the patient”)
* “Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific – oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psycho-therapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occur and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research.” -- Shapiro

Placebo: Why Use it?
* Need to control for therapeutic aspects of prescribing a medication or procedure not directly due to the medication or procedure itself
* i.e. . . . The Placebo Effect

Placebo: History
* First placebo-controlled trial:
o Sanocrysin vs. distilled water to treat TB
o 1931
The Story of Kebrozion
* Pt. with lymphosarcoma
* Patient given Kebrozion
* “The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”
* 2 months later – Kebrozion outed
* Pt given a “new form” of Kebrozion
* Water injections
* Tumors resolved remission
* 2 months later: AMA – “This stuff’s worthless”
* Pt. returns in extremis and dies

Kebrozion, Pt 2
Issues
* Does use of placebo remove access to effective standard of care?
* Is a trial that does not use placebo arm scientifically rigorous?
* Does use of a placebo sacrifice ethics and an individual patient’s welfare?

Placebo-Control: PROS
* Need placebo control to insure validity
Placebo-Control: PROS
* Need placebo control to insure validity
* Argue that no drug should be approved for patient use if it is not clearly superior to placebo or no treatment
* Scientifically invalid research is itself unethical
* Harm and discomfort nonexistent or small in some cases

Placebo-Control: PROS
* Places patients at less risk of harm due to need for smaller numbers for placebo-controlled trials
o Greater power with smaller numbers than noninferiority trial
o Many more exposed to drug in non- placebo trial
* FDA:
o Placebo controls required for disorders of moderate severity and pain
o Beta-blocker not approved for angina (even though it was shown to be as efficacious as proven tx) due to lack of placebo comparison
* Unethical to withhold effective treatment
* Places demands of science ahead of right and well-being of patients
* Your study question has to change:
o Is the new drug better than proven effective therapy?

Placebo-Control: CONS
* Patients are owed medical care for ailments when they present to healthcare providers
* Not truly testing therapy against “no treatment” placebo effect
Rothman KJ et al NEJM 1994;331:394 Enserink M Science 2000;490:418-9
* Declaration of Helsinki:
o “Every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method.”
o 2000 Revision: Placebos may be used only when there are no other therapies available for comparison with a test procedure
* “Concedes to individual investigators and to IRBs the right to determine how much discomfort or temporary disability patients should endure for the purpose of research”
Clinician/Physician Clinical Researcher
Ethical?
* Subjects: Cancer patients
* Intervention: Odansetron vs. placebo
* Indication: Post-chemotherapy emesis and nausea
* ? Proven effective therapy for nausea
* Subjects: Men with hair loss
* Intervention: Compound X vs. placebo
* Indication: Prevent hair loss
* ? Lack of sequelae from placebo use
* Subjects: Pts. with depression
* Intervention: Compound X vs. placebo
* Indication: Reduction in depressive sx.
* ? Places placebo pts. at risk for severe sequelae of depression

Ethical Balance
* Valid research vs. Undue harm
Validity Minimize Risk
Ethical Balance Validity
Minimize Risk
* Valid research vs. Undue harm
Placebo-Control and Procedures/Surgery
“A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee”
* Randomized, PLACEBO-controlled trial
* Endpoint: Pain in study knee
* Placebo:
o Did not receive general anesthesia
o Knee prepped, draped
o Three 1cm incisions made
o Knee manipulated as if arthroscopy performed
o No instruments entered the incisions
Placebo-Control and Procedures/Surgery
* Informed Consent:
o Explained study thoroughly
o Subjects had to write the following:
+ “On entering this study, I realize that I may receive only placebo surgery. I further realize that this means that I will not have surgery on my knee joint. This placebo surgery will not benefit my knee arthritis.”
o 44% declined
So . . . What do you think? Is this ethical?
Placebo-Control and Procedures/Surgery
* Placebo is not necessarily without risk
* Placebo surgery “violates an essential standard for research: the requirement to minimize the risk of harm to subjects.”
* Again – is there harm in performing an unvalidated procedure?
* Does the risk exceed that of other research procedures from which the subject does not receive benefit?
o Bronchoscopy in healthy adults
o Placement of P-A catheter in non-critically- ill subjects
o Muscle biopsy in healthy adults
* Must be informed
* Must be told that misleading tactics may be used
* Must not be misled about the chances of receiving the sham procedure
* Must be debriefed after study complete and unblinded
* Arthroscopy Study Results:
o No difference in pain scores
o The surgery itself had been causing undue risk (and cost – $3.25 billion/year)
o Without the placebo-controlled study, this would never had been discovered

Cultural Issues and Placebo-Control
* What about when conducting research in other countries?
* “Standard of care” is different due to:
o Access to meds
o Access to healthcare
o Basic infrastructure issues
o Cultural beliefs
* Prevention of fetal-maternal transmission of HIV
* Population: African women
* Intervention: Short course AZT vs. placebo
* Problem: AZT shown effective (longer course)
* Critics: Withheld effective, morbidity-reducing treatment
* Supporters: “Standard of care” in the country was no meds – no money or availability

Cultural Issues and Placebo-Control – Ethical?
* Generally felt that the cultural “standard of care” for studies in developing countries should be that of the investigator’s host country

THE USE OF PLACEBO
Placebo Acceptable If . . .
* Use of placebo does not impair health or cause “severe” discomfort
* Existing therapies only partly effective or have very serious side effects
* Low frequency of condition – would prevent enrollment for a larger trial
* Participants at risk of harm from nonresponse are excluded
* Placebo period is a limited to minimum required
* Careful monitoring is insured
* Explicit withdrawal criteria for AE
* Informed consent explicit as to why placebo should be used
* Improved survival or prevention of irreversible morbidity does not exist for any therapy
Questions

Placebo Control: What is it? Why do we use it? Is it ethical?.ppt

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