Major Depressive DisorderKathryn Secrist |Amritha Harikumar

The University of Tulsa

November 6th, 2014

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

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

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

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

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

Prevalence

12 month prevalence rate for MDD at 7%

Differs by age group; 18-29 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)

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)

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

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

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)

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)

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)

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

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

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

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)

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

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)

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)

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

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

Lifestyle and Home Remedies Pay attention to warning signs (Mayo Clinic et al., 2014)

Learn about depression

Get exercise

Avoid alcohol/illegal drugs

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

Mind-Body Techniques Acupuncture ( Mayo Clinic et al., 2014)

Yoga/Tai-chi

Spirituality

Exercise

Massage therapy

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)

Questions?

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, 107-113.

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), 245-258.

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Basso, M., Miller, A., Estevis, E., & Combs, D. (2011). Neuropsychological Deficits

in Major Depressive Disorder: Correlates and Conundrums (pp. 1-45)

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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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Huntingdon, NY by Robert Krieger). Mayo Clinic Staff(2014). Depression: Major Depressive Disorder. Retrieved from

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