This material was originally presented as a seminar for Neuroscience graduate students at the Georgetown University School of Medicine in 2008. It is taken as plain text from a Powerpoint document.
Relationships to Dream Dharma will be made and clarified and photographs and other material originally a part of the Powerpoint document will be made. There is a link at the bottom which will allow you to download the original Powerpoint presentation. Please credit the author, Talmage Carawan, and the site, DreamDharma.com, if you want to reference this material. Note that recent advances in research may have changed statements made in this now dated material, and you should of course rely on proper medical advice for any treatment.
Unipolar Depression
Major Depressive Disorder
a large area; time for just a few highlights (or lowlights?)
Sad or Major Depressive Disorder?
Clinical Presentation
Neuropharmalogy
Rx History
Animal Models
Of many SSRIs, TCAs, a brief look at Prozac
Alternative treatments
Notably, the recently approved TMS
Affordably, St Johns Wort/ Perika
Therapy, TMS, ECT, Meditation, Exercise….
Sad or Major Depressive Disorder?
Diagnostic and Statistical Manual of Mental Disorders (DSM-III, IV, IVTR)
commonly used criteria for diagnosis… MDD comes from more than one MD episode in a two month period.
The End of Sadness by Horwitz and Wakefield
A critique of the DSM criteria, citing it is too easy to categorize normal, healthy responses to problems in life as a pathology. Diagnosis as a disease may interfere with an otherwise adaptive response, making the situation worse for the individual.
Arthur Miller’s Willie Lomax in “Death of a Salesman”
Sadness with (normal, adaptive response) or without (pathological depression) cause
…However, a 15% suicide rate among those diagnosed with MDD clearly requires intervention
Selected Alternative Treatments
(time limits amount of discussion)
St. Johns Wort
Transcranial Magnetic Stimulation
Electroconvulsive Therapy
Psychotherapy and Counseling
Meditation
Acupuncture
Exercise, Lifestyle
CLINICAL FEATURES (via NIH)
According to the DSM-IV-TR (American Psychiatric Association, 2000), major depressive disorder is characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning.
Major depressive disorder is commonly recurrent and can be lethal. Up to 15% of individuals with severe major depressive disorder die by suicide. There is a 4-fold increase in death rate of individuals with major depressive disorder over 55 years of age
Clinical Features by Category
Mood
Dysphoria
Anhedonia
Pessimism and hopelessness
Excessive or inappropriate guilt
Low self esteem
Crying spells
Suicidality
Anxiety
Motor
Motor slowing
Restlessness, agitation
Clinical Features by Category, cont.
Somantic
Sleep disturbance
Abnormal appetite
Weight change
Decreased libido
Easy fatigability, low energy
Apathy, decreased drive
Cognitive
Impaired attention and short term memory
Poor executive functioning
Psychomotor retardation
SOURCE: Yudofsky and Hales APP Textbook of Neuropsychiatry and Clinical Neurosciences 4th ed
Ethology and Evolution of Depression
Bullying in childhood may lead to depression- often observed
Evolutionary role
Depressive responses following aggression and status loss, include lowered testosterone, elevated cortisol and retardation in behavior
Signals of acceptance of defeat in status contests, ubiquitous in the animal kingdom
ISS- Involuntary subordinate strategy
Ritual Agnostic Behavior
Withdrawal, lack of self-assertion, nervousness, and anxiety
Competition with the dominant animal is ceased, defeated status is accepted, and submission to winning animal signaled
Source- Horwitz and Wakefield, after Price
No single NT abnormality explains it
Noradrenergic abnormalities in depressed patients
Decreased Levels:
Urinary and plasma MHPG
Leukocyte Beta2 response (cAMP)
Hippocampal Alpha2 and Beta2 binding in postmortem brains
Increased Levels:
Plasma NE
Platelet Alpha2 binding
Serotonergic abnormalities in depressed patients
Decreased Levels:
CSF and urinary 5-HIA
CSF 4-HT
Plasma tryptophan
Platelet 5-HT uptake and platelet imipramine binding
Plasma 5-HT
Imipramine binding in postmortem brains
Increased Levels:
5-HT (2) receptor binding in brains of suicide victims
Other NT abnormalities- Dopamine, opiates, GABA, acetylcholine
(Partial list… see Table 31-3 in Yudofsky and Hales)
Genetics FROM NIH OMIM (Mendelian Inheritance)
chromosome 12q22-q23.2
chromosome 12q22-q23
Polymorphism in the FKBP5 gene
mutation in the tryptophan hydroxylase-2 gene (12q21 mapping enzyme of serotonin synthesis)
A polymorphism in the HTR2A gene (encodes serotonin 2A receptor)
Animal Models
One perspective- The Olfactory Bulbectomized Rat as a Model of Major Depressive Disorder- Neuromethods vol 19- J. Steven Richardson
problems reflect philosophical positions ranging from those based on the premise that primary depression does not fit the medical model and therefore is not a “disease” that can be modeled, to those holding that the emotional state of depression is so uniquely human that subhuman organisms cannot be used in its analysis.
More pragmatically, we have (e.g.) forced swimming, climbing, and mouse tail suspension test. (full references may be supplied)
Potentiation of the Antidepressant-Like Effect of Fluoxetine by Aripiprazole in the Mouse Tail Suspension Test
Confirmation of antidepressant potential of the selective beta3 adrenoceptor agonist amibegron in an animal model of depression. (forced swimming)
Depressive-like behavior and high alcohol drinking co-occur in the FH/WJD rat but appear to be under independent genetic control (Next slide….)
Rat model, cont.
The fawn-Hooded rat (FH/Wjd) exhibits co-occurring depressive-like behavior and high alcohol intake independently. The FH/Wjd rat is both highly immobile in the forced swim test and drinks substantial amounts of 5-10% alcohol voluntarily.
The FH/Wjd serves as an animal model of alcoholism (becomes tolerant, becomes dependent and expresses withdrawal symptoms, bar-presses for alcohol). Other literature in addition to the high swim test immobility suggests that the FH/Wjd rat may also be an animal model of depression (high basal corticosterone levels, blunted hormonal responses to serotonergic agonists)
Modern Depression Rx History
19th Century Opium, morphine
Early 20th Barbituate sedatives
1950s Miltown- Meprobamate, a tranquilizer,
MAOIs, TCA (imipramine and amitriptyline)
by 1956, 1 in 20 Americans took tranquilizers
1960s Valium, Librium
Rolling Stones “Mother’s Little Helper”
1980s SSRIs, with Prozac becoming very popular in the 90s
Managed health care
Direct to Consumer Advertising started in 1997
(source- Horwitz and Wakefield)
Prozac: A common Rx
Two common medication types- TCA and SSRI; Prozac is a SSRI
SSRI- Selective Serotinin Re-Uptake Inhibitor
TCA- Tricyclic antidepressant- less commonly used as more serious side effects (weight gain, confusion, cardiovascular problems, easy to take overdose)
Prozac Rx Notes
Used to treat Depression, OCD, Panic Disorder, Bulimia
1st Warning by Lilly is Increased Risk of Suicide thought and behavior (compared to placebo), particularly in those less than 24 y.o.
Structure of Fluoxetine
(±)-N-methyl-3-phenyl-3-[(α,α,α trifluoro-p-tolyl)oxy]propylamine hydrochloride
C17H18F3NO•HCl
molecular weight is 345.79
Side effects: drowsiness, nervousness, insomnia, tremor, dizziness, headache, confusion, paresthesia, nausea, sexual dysfunction, weight loss
May take 8 weeks to reach steady state
Inhibition of 5-HT re-uptake, increasing 5-HT in synapse
Inhibition of hepatic cytochrome P450 2D6 enzyme (also 2C, 3A(4))
#Zung Depression Self-Assessment Test on prozac.com website(is it too easy to be diagnosed?)
NIH Medline gives an A grade to St. Johns Wort
Short-term studies (1-3 months) suggest that SJW is more effective than placebo (sugar pill), and equally effective as tricyclic antidepressants (TCAs) in the treatment of mild-to-moderate major depression.
Comparisons to the more commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac) or sertraline (Zoloft), are more limited.
However, other data suggest that SJW may be just as effective as SSRIs with fewer side effects.
Hypericin may inhibit dopamine enzyme β-hydroxylase, leading to increased DA and drops in norepinephrine and epinephrine.
Wide variety of supplement formulations and claims- wide ranging doses (10x conc difference), sources (e.g. stem leaf flower), and purification method of Hyperforin (Hypericum and other spellings may be encountered.)
Perika better substantiated than most- made by Schwabe in Germany, demonstrated superior to other SJW products in clinical trials, distributed by Nature’s Way in US
(Note- contradictory statements exist in NIH websites; however, testing supports the above)
Transcranial Magnetic Stimulation (TMS)
Recently approved by the FDA for treatment in patients who have not responded to at least one antidepressant medication
Very minor side effects compared to other treatments
On HAMD testing, > 50% patients show significant improvements, with 33% cases in remission
Magnetic pulses stimulate left prefrontal cortex, using a non invasive device; 3000 200uS pulses induce electric current to flow in brain via neuron activation
20-30 sessions over 4-6 wks, 37 minute treatment
$6-10K cost for treatment series (for investigational use only at this time)
May be useful for schizophrenia, PTSD, migraine
Possibly valuable treatment for teens who have higher risk of suicide on medications
Web link to video http://www.neuronetics.com/howtmsworks.html
Meditation
Controlling mind and body with the mind
Many choices, very affordable, coupled with spiritual and/or physical exercises (Insight meditation, Mahamudra, Tonglen, Zen/ Dzogchen (non meditation as meditation), Tai Chi, hatha yoga…
Well documented and easily demonstrated benefits in calming, lowering of BP, concentration, awareness
Some may consider it time consuming, others life saving.
And there was music, and there were wonderful roses… they tell me, in sweet fragrant meadows of dawn, and dew… There was love, all around, but I never heard it singing… No, I never heard it at all, till there was you. -Meredith Wilson, from “The Music Man”
And what of love and music and acupuncture and exercise… but that’s all the time we have for now… Relax, be happy!
Dream Dharma ~ ~ ~ ~ 