Major Depressive Disorder: Diagnosis, Biology and Treatment Jeffrey Rakofsky, MD Department of Psychiatry and Behavioral Sciences Emory University School of Medicine Atlanta, Georgia, USA Conflict of interests

• In the last three years, I have received research funding from Assurex, Takeda, AstraZeneca Learning Objectives Upon completion of the lecture, the learner should be able to… 1. Describe the symptoms and consequences of major depressive disorder

2. Explain the epidemiology, genetics and biology associated with the illness

3. List the various treatment options available CLINICAL What is MDD?

• A mood disorder

• More than just feeling blue or feeling down

• A medical illness that includes: Sadness + Changes in body functioning + Impairment Diagnosis of MDD

• Medical illness must be ruled out

• No definitive brain imaging or biomarkers

• Clinical interview: rule in MDD, rule out Bipolar disorder and other depressive illnesses Other depressive disorders

• Bipolar depression

• Persistent depressive disorder

• Depression due to another medical condition

• Substance-induced depressive disorder Symptoms (M-SIGECAPS)

• Mood (depressed) • Sleep • Interest • Guilt/worthlessness • Energy • Concentration • Appetite • Psychomotor changes • Suicide DSM-5 rules for diagnosis

• 5 of the 9 symptoms

• 1 must be depressed mood or decreased interest

• Must cause impairment Additional symptoms

• Psychosis

• Anxiety Cognitive dysfunction

Domain affected Result Attention Difficulty concentrating Loses track of thoughts Memory Forgetfulness Executive function Inability to decide, Inability to multi-task Psychomotor speed Foggy brain

• Worsens with each new episode • Impacts function • Among the most common residual symptoms • Inter-episode cognitive function is related to the number of previous episodes Information processing errors

• All or nothing thinking

• Overgeneralization

• Negative filter

• Discounting positives

• Jumping to conclusions

• Magnification/minimization

• Emotional reasoning

• “Should” statements

• Labeling

• Personalization and blame Functional impairment MDD is the 2nd leading cause of disability worldwide!

Ferrari et al. Plos Medicine. November 2013. Health impact

• Depression worsens overall health care outcomes

 Greater impact than angina, arthritis, asthma or diabetes

 Predicts death in the six months following a myocardial infarction

 Patients with depression are 2-4x more likely to have an adverse health care outcome Suicide

• 10-15% of patient with MDD die by suicide

• 60% of those who die by suicide have depression

• Some survive with catastrophic injuries

Risk factors for attempt Risk factors for completion Total time spent in episode Alcohol abuse/dependence Symptom severity Drug abuse/dependence Previous attempts Impulsivity Lack of a partner Aggression Lack of social support Recent psych hospitalization Course of illness

• Recovery= 70% within the first year, 20% remain depressed by end of two years

Risk of recurrent episode: 50% if one previous episode

70% if two previous episodes

90% if three previous episodes

Course of illness

• Post-partum

• Seasonal

• Pre-menstrual Comorbidities

• Anxiety disorders (50%)

• Substance use disorders (24%)

• Personality disorders (50-85%)

• Medical disorders (e.g. cancer 10% vs. 1%) THE SCIENCE Epidemiology

• Lifetime prevalence = 16.6%

• Male: Female ratio = 1:2

• Median age of onset = 32 years old

Genetics

• Heritability is 50%

• Adoption studies: 67% vs. 9%

• Multiple genes

• Genetic x environment interaction (early life trauma) Genetic Risk • If you are a member of the general population, risk of developing MDD = 10%

• If you have a first-degree relative, risk of developing MDD = 20-30%

• If the first-degree relative has recurrent episodes of MDD or early onset (childhood-early 20’s), risk of developing MDD = 40-50%

Biology

• Neuro-circuitry disruption

• “Chemical Imbalance”

• Inflammation TREATMENTS Medications

• Serotonin reuptake inhibitors

• Serotonin norepinephrine reuptake inhibitors

• Atypical antidepressants

• Tricyclic antidepressants

• Monoamine oxidase inhibitors Medications

• Continuation treatment for 9-12 months after remission

• Maintenance treatment recommended if:

 3 lifetime episodes, or

 2 episodes with high severity (psychotic, highly suicidal) Antidepressants and youth

• 2004 FDA issues black box warning for all antidepressants: Patients 24 years old and younger may have increase in suicidal thinking and/or behavior • Led to a decrease in antidepressant prescriptions for youth • Increase in non-fatal drug poisonings of 21.7% among adolescents and 33.7% among young adults in the second year after FDA warning • Increase in suicides of 18% among 10-19 year olds in the first year after FDA warning • Studies in 2012 reanalyzing data do not show increased suicidality for youth (and no completed suicides) Psychotherapy • Cognitive Behavioral Therapy (CBT)

• Interpersonal Therapy Dietary supplements

• Omega 3 fatty acids, SAMe, L-methylfolate, Vitamin D

• Monotherapy and augmentation

• May increase neurotransmitter production and/or reduce inflammation

• Buyer beware! Diet

• Mediterranean diet studied most commonly

• Effective in prevention

• Anti-oxidant and anti-inflammatory effects

Exercise

• Monotherapy and augmentation

• Aerobic > resistance training

• 3 times per week for 45-60 mins

• Intensity= 50-85% of HRmax (aerobic); 3 sets of 8 reps at 80% of 1-RM (resistance) Light box therapy

• Treats non-seasonal and seasonal forms of major depression

• Resynchronizes circadian rhythms

• 10,000 lux x 30 minutes upon awakening

• Few side effects Electroconvulsive Therapy (ECT)

• Seizure induced by medical staff while patient anesthetized

• Is very effective and has rapid anti-depressant effects

• For patients with treatment-resistant depression or with high suicide risk

• 3x per week up to 12 sessions initially

• Side effects: short-term memory loss, long-term memory loss, headaches Reduces hyperconnectivity Repetative Transcranial Magnetic Stimulation (rTMS) • Application of magnetic coil at the skull surface

• Administered in 45- minute sessions, 5 days per week, for 4-6 weeks

• 50% response rate in naturalistic studies

• A good option for those who can’t tolerate medications or those Side effects: mild headaches, scalp discomfort who are considering ECT Ketamine

• Rapid antidepressant and anti-suicidal effects

• Not simply a euphoric effect

• Administered through intravenous Infusions or intranasal sprays

• Cognitive and bladder side effects Deep Brain Stimulation

• Experimental treatment used in Parkinson’s disease

• Surgical implantation of electrode into the subgenual cingulate cortex or other targets

• Directly turns on or off brain circuits that regulate mood

• 60% of TRD patients responded by 1 year Conclusions

• Major depression is a mood disorder that can impact function, quality of life and health outcomes

• It is a brain illness that gets passed on from generation to generation

• A number of effective treatment options exist for those with the mildest forms and for those with the most severe forms of depression Questions???

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