1. Major Depressive Disorder
Kathryn Secrist |Amritha Harikumar
The University of Tulsa
November 6th, 2014

2. Clinical Presentation
Major Depressive Disorder(MDD) is a disorder that presents specific symptoms according to the DSM-V( American Psychological Association., 2013)
According to the DSM-V, the Diagnostic and Statistical Manual of Disorders-5th Edition, five or more of certain symptoms have to be present in the patient during a continuous 2 week period; one of the symptoms includes depressive mood or loss of interest or pleasure:
Depressed mood most of the day; nearly every day with symptoms such as sadness, emptiness, hopelessness and irritability (DSM-IV)
Loss of interest/pleasure in daily activities
Marked weight loss without diet/exercise changes during regular routines; OR decrease/increase in appetite every day
Psychomotor agitation/retardation
Fatigue, loss of energy
Excessive guilt/feelings of worthlessness
Diminished ability to think/concentrate
Suicidality
Symptoms above cause clinically significant problems/stress
IMPORTANT: Cannot be caused by substance abuse/medical condition

3. Essential Features of MDD
Criterion symptoms must be present close to every day ( APA et al., 2013)
Fatigue/sleep disturbances common in MDD
2 weeks of depressed mood/loss of interest-KEY FEATURE OF MDD
Four additional symptoms must be present that include the following:
Appetite/weight increase-decrease
Psychomotor activity
Decreased energy
Feelings of worthlessness
Difficulty thinking/concentrating

4. Depression in History
Initially called “melancholia” (Nemade, Reiss, & Domback., 2007)
Earliest accounts of melancholia appeared in ancient Mesopotamian texts
All mental illnesses at this time were attributed to demonic possession
The first historical understanding of depression was a spiritual illness rather than a physical one.
Hippocrates, a Greek physician, thought that melancholia was caused by too much black bile in the spleen.
In the years before Christ, Romans believed in demonic possession while Persians viewed the brain as the seat of melancholia

5. Depression in History
After fall of the Roman empire, scientific thinking about the causes of depression again regressed (Nemade et al., 2007)
During the Middle Ages, religious beliefs dominated popular European explanations of mental illness e.g. demons and witches
Treatments included exorcisms, drowning and burning
During the Renaissance, some doctors returned to the views of Hippocrates
During the beginning of the Age of Enlightenment, it was thought that depression was an inherited, unchangeable weakness of temperament.
Lead to the common thought that affected people should be shunned or locked up. (Nemade et al.,2007)
In latter part of Age of Enlightenment, some doctors and authors suggested that aggression was the real root of depression
Advances in general medical knowledge caused search for organic (physical) treatments

6. Depression in History
Towards the beginning of 19th century, new therapies included water immersion and a spinning stool to induce dizziness. (Nemade et al., 2007)
Benjamin Franklin introduced an early form of electroshock therapy.
First distinguished from schizophrenia in 1895
In 1917, Sigmund Freud explained melancholia as a response to loss
Either real loss, or symbolic loss
Freud believed that a person’s unconscious anger over loss weakened the ego, resulting in self-hate and self-destructive behavior (Nemade et al.,2007)
In the 1950s and 1960s, the medical community classified depression as either “endogenous” or “neurotic”
Currently, medical professionals recognize that depressive symptoms have multiple causes

7. Prevalence 12 month prevalence rate for MDD at 7%
Differs by age group; year olds have three times more of a prevalence rate than people 60 years of age and older (Kessler, Berglund, & Demler., 2003)
Women are twice more likely to have depression than males (Kessler et al.,2003)
Attributed to genetic factors, especially first degree relatives (Kendler, Thornton, & Gardner, 2001)
Patients w/higher levels of neuroticism and brain trauma at greater risk for developing MDD (Kendler et al., 2001; Basso, Miller, Estevis, & Combs., 2011)

8. Course of Illness
Extremely variable, depends on remission rates which vary per person (some people experience MDD after 2 months with either zero symptoms; or 1-2 symptoms)
Important to distinguish between individuals who developed depression and are undergoing treatment after a long period of symptoms versus individuals who recently developed MDD
In the latter case, it is labelled chronic depressive symptoms, and can develop because of personality, anxiety, and extraneous factors (Coryell, Endicott, & Keller., 1990; Klein, Taylor, & Dickstein., 1988)
Recovery: Occurs 3 months after initial diagnosis in 2/5 patients, and within one year for 4/5 individuals (Coryell, Akiskal, & Leon., 1994)

9. Genetic and Environmental Factors
First-degree family members of individuals with major depressive disorder have a risk for major depressive disorder two- to fourfold higher than that of the general population (APA et al., 2013)
Relative risks appear to be higher for early-onset and recurrent forms
Approximately 40% heritability
The personality trait neuroticism accounts for a substantial portion of genetic liability
Adverse childhood experiences constitute a set of potent risk factors for MDD
Stressful life events are well recognized as precipitants of MDD ( APA et al., 2013)
But the presence or absence of adverse life events near the onset of episodes is not a useful guide to prognosis or treatment selection

10. Unipolar Depression
No pathogenomic distinctions between unipolar and bipolar depression
Major difference between unipolar and bipolar individuals is the development of hypomania (thus making the patient “bipolar”) (Mitchell, Goodwin, Johnson, Hirschfield, 2008).
Common features in unipolar depressive disorder include:
Insomnia/lessened sleep
Appetite loss
Later age of onset concerning MDD
No family history of BP disorder
Normal or increased level of activity
Prolonged episodes
Two sub-types of unipolar depression- atypical and agitated depression (Mitchell et
al., 2008).
Controversial subtypes due to comorbidity issues in both agitated and atypical
depression

11. Agitated Depression
Also referred to in the literature as “depressive mixed state”
Primary symptoms:
Restlessness,
Increases talkativeness
Irritability (Akiskal, Benazzi, Perugi, & Rihmer, 2005; Kraeplin,1899, 1921 English translation by Barclay; Weygandy, 1899, English translation by Marneros in 2001)
Issues with diagnosis, due to comorbidity with bipolar disorder
35% of unipolar depressed patients will display agitated depressive symptoms(Akiskal, Benazzi, Perugi, Rihmer., 2004)

12. Atypical Depression
Mood reactivity, must have two of the following symptoms:
Significant weight gain
Hypersomnia
Leaden paralysis
Long history of rejection sensitivity(APA., 2013)
16-23% of unipolar patients show atypical depressive symptoms(Benazzi .,1999)
Comorbidity issues with BP-1 disorder(Mitchell et al., 2008)
“Atypical” symptoms such as hypersomnia, leaden paralysis, psychomotor agitation, psychotic features, pathological guilt(Mitchell et al., 2008)

13. Neural Structures of MDD
Medial orbital pre-frontal cortex, amygdala, hippocampus, ventromedial parts of basal ganglia; alterations in gray matter volume all implicated in individuals with major depressive disorder
Dorsal medial prefrontal cortex was implicated, supragenual anterior cingulate cortex, precuneus, ventral striatum, and the dorsomedial thalamus(Grimm, Ernst, Boesiger, Schuepback, Hell, Boeker, & Northoff., 2009)
Signal changes in DMPRFC mediated depression severity and hopelessness
Ventral striatum and Dorsomedial thalamus relate to judgements of self- relatedness of negative emotional stimuli(Grimm et al., 2009)

14. Neurotransmitters Involved
Monoamine deficiency is among the oldest of the neurochemical theories of depression (Holtzeimer & Nemeroff., 2006)
Serotonin, norepinephrine, and dopamine are widely distributed throughout the central nervous system
Involved in many aspects of behavior including mood, cognition, locomotion, sleep, appetite, libido, arousal, anxiety, and aggression
Largely function as modulators of excitatory and inhibitory neurotransmitter circuits (Holtzeimer et al., 2006)
Considerable overlap exists between these systems

15. Serotonin Produced in cells of the rostral and caudal raphe nuclei
Serotonergic projections include several brain regions, including the hypothalamus, thalamus, hippocampus, amygdala, basal ganglia, prefrontal cortex, and cingulate cortex (Holtzeimer et al., 2006)
The effects of serotonin are mediated through pre and postsynaptic 5HT receptors
After release from the presynaptic terminal, 5-HT binds to 5-HT receptors or is taken up into the presynaptic terminal by the serotonin transporter and either repackaged into a terminal vesicle or catabolized by monoamine oxidase
Cerebrospinal fluid levels of serotonin metabolites are generally reduced in depressed patients and even lower in depressed patients with a history of suicide attempts
Tryptophan depletion can lead to a depressive relapse in euthymic patients with history of depression responsive to SSRIs (Holtzeimer et al., 2006)
Reduced SERT availability and binding abnormalities have been consistently identified in depression

16. Norepinephrine
Primarily produced in cells of the pontine locus ceruleus (Holtzeimer et al., 2006)
These cells project to multiple cortical and subcortical brain regions
NE system well known to modulate the stress response
NE interacts with pre and postsynaptic alpha and beta-adrenergic receptors
Following release from the presynaptic terminal, NE is taken back up into the presynaptic terminal by the norepinephrine transporter where it is either repackaged or metabolized by MAO (Holtzeimer et al., 2006)
Role in the pathophysiology of depression is fairly well-established but less clear than 5-HT and dopamine

17. Dopamine
Transmission primarily organized into three distinct systems within the brain
Nigrostriatal pathway
Mesolimbic-mesocortical pathway
Periventricular system (Holtzeimer et al., 2006)
DA exerts effects at DA receptors and is taken up into the presynaptic terminal via the DA transporter
DA nerve terminals in prefrontal cortex contain no DAT, and DA signal is inactivated by uptake into nearby NE nerve terminals by NET.
DA precursor for NE, but role in depression far less scrutinized
CSF concentrations of DA-homovanillic acid are decreased in depressed patients, and urine levels of DOPAC have been shown to be decreased in depressed patients and potentially associated with suicidal behavior
DA neurons are reduced in activity in depression (Holtzeimer et al., 2006)

18. Treatment Specific medications such as:
SSRIs (selective serotonin reuptake inhibitors)-fluoxetine (Prozac, paroxetine(Paxil), sertraline(Zoloft), citalopram(Celexa), escitalopram(Lexapro)
Safer, contains less side effects (Mayo Clinic., 2014)
SNRIs (serotonin and norepinephrine reuptake inhibitors
Duloxetine- Cymbalta
Venlafaxine (Effexor XR)
Desvenlafaxine (Pristiq)
Norepinephrine and dopamine reuptake inhibitors(NDRIs)
Buproprion(Wellbutrin)- anti depressant with few sexual side effects
Atypical Anti-depressants (Mayo Clinic et al., 2014)
Trazodon
Mirtazapine (Remeron)
Sedating and usually need to be take in the evening
Vilazodone-(Biibryd)- newer medication, low risk of sexual side effects

19. Treatment cont’d Tricyclic anti depressants (Mayo Clinic et al., 2014)
Tofranil- imipramine
Notryptilin- Pamelo
Tend to cause more severe side effects than anti-depressants; aren’t prescribed unless SSRIs are ineffective
Monoamine oxidase inhibitors(MAOIs) (Mayo Clinic et al., 2014)
Tranylcypromine(Parnate)
Phenelzine(Nardil)
Serious side effects involved with MAOIs
Specific with certain foods
Certain cheeses, pickles, and wines
Medications that contradict include birth control pills, decongestants, and herbal suppressants
Other medications
Doctors may combine two or more antidepressants to increase its power, as well as antipsychotics and mood stabilizers (Mayo Clinic et al., 2014)

20. Psychotherapy
General term concerning treating depression by talking out feelings/thoughts/concerns one may have about their condition
Known as talk therapy, counseling, or psychosocial therapy
Different types of psychotherapy include
Cognitive behavioral therapy(CBT)
Interpersonal therapy
Dialectic behavior therapy
Acceptance and commitment therapy
Mindfulness techniques (Mayo Clinic et al., 2014)

21. Benefits of Therapy
Adjusting to a crisis/difficulties in life (Mayo Clinic et al., 2014)
Looking at negative people behaviors, changing it to positive behaviors
Develop positive interactions with others
Coping and solving problems
Ways to decrease depressive triggers
Regaining control/happiness in one’s life
Realistic goal setting
Generally developing healthier behaviors in order to solve problems

22. Hospitalization/Treatment Options
In-patient vs. Outpatient (Mayo Clinic et al., 2014)
In patient more necessary for serious conditions
Psychiatric hospitals
Day treatment programs
Other treatment options
Electroconvulsive Therapy (ECT)
Electric currents passed through the brain
Affects neurotransmitters, offer temporary relief of severe depression
Other side effects: memory loss
Transcranial Magnetic stimulation
Good option for individuals that don’t respond well to antidepressants
Involves sitting in a reclining chair with a magnetic coil placed with scalp
Brief magnetic pulses are sent to the scalp; stimulates nerve cells crucial to MDD
Five treatments for six weeks

23. Lifestyle and Home Remedies
Pay attention to warning signs (Mayo Clinic et al., 2014)
Learn about depression
Get exercise
Avoid alcohol/illegal drugs

24. Alternative Medicine
St. John’s Wort- Popular depression treatment in Europe (Mayo Clinic et al., 2014)
Interferes with a number of medications
Interferes with antidepressants
HIV/AIDS medications
Birth control pills
Sam-E: Dietary supplement that is a synthetic form of S-adenosyl_L- methionine
Isn’t approved by FDA, however is approved in Europe
More research needed; may trigger BP depression
Omega-3 Fatty Acids
Found in cold water fish, flaxseed, flax oil, walnuts, other foods
Studied as a possible treatment for depression
May interact with other medications
More research needed

25. Mind-Body Techniques Acupuncture ( Mayo Clinic et al., 2014)
Yoga/Tai-chi
Spirituality
Exercise
Massage therapy

26. Future Research
Identifying various factors as well as subtypes of MDD, such as genetic, environmental, course of illness, and symptoms (Hunter.,2013)
Predicting onset, recurrence, and co-occurring illness; environmental factors that affect genetic pre-disposition in individuals; prevention of co- occurring illness (Hunter et al., 2013)
Focusing on childhood developmental factors that may influence onset of disorders at adulthood(relevant psychological, social, biological events); specific behavioral patterns from childhood—adult life
Advancing information with the help of neurobiology and imaging techniques
Physiological processes of aging and depression patterns related to this (Hunter et al., 2013)
Identifying biological markers for depression in the blood or through brain imaging and being able to customize treatment for individuals based on this information (Hunter et al., 2013)

27. Questions?

28. References
Akiskal, H.S., Benazzi, F. (2004). Validating Kraeplin’s two types of depressive mixed states: Depression with flight of ideas and
Excited depression. World Journal Biological Psychiatry, 5,
Akiskal, H. S., Benazzi, F., Perugi, G., & Rihmer, Z. (2005). Agitated “unipolar”
depression re-conceptualized as a depressive mixed state: Implications for the
antidepressant-suicide controversy. Journal of Affective Disorders- Elsevier, 85(3),
Retrieved March 18, 2013.
American Psychiatric Association (Ed.). (2013). Diagnostic and Statistical Manual of Mental
Disorders: DSM-5. Retrieved November 5, 2014, from
dsm.psychiatryonline.org.library.utulsa.edu/doi/book/ /appi.books
Basso, M., Miller, A., Estevis, E., & Combs, D. (2011). Neuropsychological Deficits
in Major Depressive Disorder: Correlates and Conundrums (pp. 1-45)
Benazzi, F. (1999). Bipolar II versus unipolar chronic depression : A 312 case study. Comprehensive Psychiatry,
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Coryell, W., Endicott, J., Keller, M. (1990). Outcome of patients with chronic
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Coryell, W., Akiskal, HS., Leon, AC.(1994). The time course of non-chronic
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Grimm, S., Ernst, J., Boesiger, P., Schuepbach, D., Hell, D., Boeker, H., Northoff, G. (2009). Increased self – focus in major depressive disorder is related to neural
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29. References
Hunter, J. (2013). Research on Depression. Retrieved November 5, 2014, from
Kendler, K. S., Thornton, L. M., & Gardner, C. O. (2001). Genetic risk, number of
previous depressive episodes, and stressful life events in predicting onset of major
depression. American Journal of Psychiatry, 158,
Kessler RC, Berglund P, Demler, O. (2003) The epidemiology of major depressive
disorder: results from the National Comorbidity Survey Replication (NCR). Journal of
American Medical Association,  289(23), 3095–3105
Klein, DN., Taylor, EB., Dickstein, S ., Harding, K(1988). Primary early-onset dysthymia :
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clinical, familial, personality, and socioenvironmental characteristics and short-term
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Kraepelin, E., (1899, 1921, English translation). Manic-depressive insanity and paranoia.
Translated by R.M. Barclay, Edingburgh, E & S. Livingstone (reprinted in 1976 in
Huntingdon, NY by Robert Krieger).
Mayo Clinic Staff(2014). Depression: Major Depressive Disorder. Retrieved from
Mitchell, P.B., Goodwin, G.M., Johnson, G.F., Hirschfield, RMA. (2008). Diagnostic Guidelines for bipolar depression: a probabilistic approach
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