Unipolar Depression Steven L. Dubovsky, M.D..

Unipolar Depression Steven L. Dubovsky, M.D.

Objectives Discuss the nature of mood disorders
Clarify diagnostic subtypes of unipolar depression Describe presentations of depression in outpatients and younger patients Explain neurobiological and psychological factors Outline course and treatment

What is a Mood Disorder? Behavior Mood Thought Vegetative Function

Features of Depression
Change in mood Sad Irritable Anxious No emotion Change in thinking Negative expectations Guilt Low self-esteem Indecisiveness Suicidal thinking Change in vegetative function Loss of pleasure (anhedonia) Sleep disorder Appetite disturbance Low energy/motivation Circadian variation of mood Aches and pains

Major Depressive Episode
Depressed mood or anhedonia (loss of pleasure) At least 5 of the following symptoms for at least 2 weeks: Depressed mood most of the time Anhedonia Significant weight change Insomnia or hypersomnia Agitation/retardation Fatigue or loss of energy Feelings of worthlessness or guilt Problems concentrating or indecisiveness Recurrent thoughts of death or suicide

Point Prevalence of Depression
Community: 2-4% Primary care clinic: 5-10% Medical inpatients: 10-14% Nursing home: 6-25%

Epidemiology of Depression
Incidence Men: 4-10% Women: 10-25% Point prevalence Community: 2-4% Primary care clinic: 5-10% Medical inpatients: 10-14% Nursing home: 6-25%

Functioning in Chronic Illness
HBP Arthritis

Impact of Depression on Medical Outcomes
50% increase in cost of care Increased morbidity and mortality from diabetes and heart disease 1.4-fold increased risk of out of hospital cardiac arrest W Katon: Biol Psychiatry 2003;54:216

Cost of Depression Total annual cost: $43.7 billion
Hirschfeld: JAMA 1997;277:333

Secular Changes in Epidemiology of Mood Disorders in 20th Century
Increasing incidence Younger age of onset Increasing severity and complexity More violent bipolar adolescents

Why is the Incidence of Mood Disorders Increasing?
Assortive mating Accumulation of genetic risk Anticipation (discussed with bipolar lecture) Decreased modulation of arousal by families Increased exposure to overstimulation in media Increased treatment of younger patients with antidepressants and stimulants Loss of regulation of inflammation due to elimination of benign microorganisms

Subtypes of Unipolar Depression
Major depressive episode Major depressive disorder (recurrent unipolar depression) Atypical depression Psychotic depression Dysthymia (persistent depressive disorder) Mood disorder due to a general medical condition (secondary depression) Substance induced mood disorder

Psychotic Depression (Major Depression with Psychotic Features)
Delusions and/or hallucinations Compared to nonpsychotic depression: More severe More recurrent Greater familial prevalence of mood disorders, psychotic depression, schizophrenia Less likely to respond to antidepressants More likely to require antipsychotic drug added to antidepressant More likely to have bipolar outcome

Seasonality and Mood 70% of depressed patients feel worse in winter
Peaks when days are shortest Not linked to holidays Non-depressed people feel more sluggish in winter and livelier in summer Cabin fever and summer activation Suicide peaks in the spring NOT at holidays Seasonal affective disorder

Seasonal Affective Disorder (Seasonal Specifier)
Depression begins in fall or winter Earlier at latitudes with greater seasonal variation in available daylight Ends in spring Normal mood or hypomania in spring and summer Reverse pattern in southern hemisphere Responds to artificial bright light Mood changes linked to changes in available daylight More frequently bipolar than non-seasonal depression

How is Childhood Depression Different from Adult Depression?
Irritability, social dysfunction and behavioral problems more obvious than depressed mood Vegetative symptoms not as clear More hypersomnia and lethargy More familial loading Greater impact of social factors Lower chance of antidepressant response Bipolar outcome more likely

Presentations of Depression in Children
Apathy Irritability Anxiety Appetite disturbance Increased sleep Loss of interest Withdrawal Slide 1

Presentations of Depression in Children
Problems concentrating Poor school performance Oppositional attitude Antisocial behavior Substance abuse Slide 2

Medical Illnesses that Commonly Cause Depression
Endocrine disease Hypo- and hyperthyroidism Cushing’s and Addison’s Hypercalcemia Diabetes mellitus Malignancy and hematologic Pancreas Breast Brain Lung Paraneoplastic Lymphoma Anemias Pernicious anemia Slide 1

Neurological Traumatic brain injury Parkinson’s disease Left prefrontal and basal ganglia CVA Huntington’s disease Brain tumor Dementia Slide 2

Infectious HIV Mononucleosis Hepatitis Autoimmune disease SLE Rheumatoid arthritis Fibromyalgia Slide 3

Medicines that Commonly Cause Depression
Acyclovir Amantadine Anabolic steroids Asparaginase Beta adrenergic blockers Benzodiazepines Bromocriptine, pergolide Diltiazem, nifedipine Digitalis Disulfiram Slide 1

Medicines that Commonly Cause Depression
Interferon alfa Levodopa Methyldopa, reserpine, clonidine Isotretinoin Theophylline Trimethoprim-sulfamethoxazole Vincristine, vinblastine Zidovudine Slide 2

Substances that Commonly Cause Depression
Alcohol Stimulants Sedatives Tranquilizers Narcotics

Family Studies of Mood Disorders
First degree relatives of patients with unipolar depression: Risk of unipolar depression: % Risk of bipolar disorder: % First degree relatives of patients with bipolar disorder Risk of unipolar depression: % Risk of bipolar disorder: %

Adoption Studies Greater incidence of unipolar depression in biological than adoptive relatives of unipolar patients

Twin Studies MZ:DZ overall concordance for mood disorder = 3:1
Concordance rates for unipolar depression: MZ: 0.50 DZ: 0.20

Oligogenic Inheritance
Gene 2 Gene 1 Disease Gene 3

Action Planning Memory Biological Rhythms Emotion Arousal

Institutions Other People Beliefs Individual Religion Groups Ideas

Mood Disorder - + NE CRF ACTH Cortisol Pituitary Adrenal Amygdala
Hypothalamus Locus Coeuruleus NE - CRF Pituitary ACTH Adrenal Cortisol

Antidepressants and HPA Axis
Therapeutic action of antidepressants correlated with decreased CSF CRF Depression may be mediated by CRF-1 receptors in limbic structures CRF-1 antagonists inhibit deleterious effect of stress on neurogenesis G Racagni, Popoli M: Int Clin Psychopharmacology 2010;28:117

Biological Markers Nonsuppression on DST 40-50% in MDD
80-90% in psychotic depression, bipolar disorder Hypersecretion of CRF State variable Return of nonsuppression in remitted patient predicts relapse False positives with weight loss, smoking, alcohol, hospitalization, some medications Slide 1

Biological Markers TRH stimulation test
Blunted in 1/3 of melancholic depressed patients Overlap with DST variable Slide 2

Biological Markers Sleep Decreased sleep continuity More awakenings
Decreased REM latency Increased REM density Decreased slow wave sleep Trait or state variable Slide 3

Imaging Findings Similar in unipolar depression in older patients and bipolar disorder at any age Enlarged third and lateral ventricles Reduced frontal lobe volume Loss of hippocampal volume Reflects duration of illness not age of patient May persist long after depression remits Hyperactivity of amygdala, medial thalamus, orbital and medial PFC, ventral striatum (limbic system)

Implications of Imaging Findings
Neuronal atrophy may be a consequence of unrestrained or recurrent stress response Neurotoxicity of cortisol and excitatory amino acids Reversible after early but not later episodes Loss of neurons in frontal lobes impairs planning and problem solving Loss of hippocampal neurons results in Reduced ability to retrieve memories necessary for responding to new challenges Progressive loss of regulation of sympathetic nervous system

Excessive stress response Everyday challenge
Recurrent stress Hypersensitive CRF neurons Deficient coping Negative cognitions Affective arousal Hypercortisolemia Hippocampal damage Impaired cognition Reduced problem solving

Neurotransmitter Interactions
5HT DA NE

Monoamine Neurotransmitters

Neurotransmitter Summary

Other Neurotransmitters Implicated in Depression
Vasopressin Antidepressants decrease AVP levels V1B and V3 antagonists may have antidepressant effects Neuropeptide Y Decreased CSF NPY in depression SSRIs increase CSF NPY

Receptors All antidepressants except ECT down-regulate beta adrenergic receptors Brains of suicides have down-regulated beta receptors Many antidepressants down-regulate serotonin 5HT2 receptors Antidepressants decrease expression of NR1 subunit of NMDA receptor in hippocampus Memantine has antidepressant properties Tianeptine inhibits glutaminergic neurotransmission G Racagni, M Popoli: Int Clin Psychopharmacology 2010;25:117

Inflammation Pro-inflammatory cytokines can induce depression
Inflammatory proteins increased in depression CRP TNF TNF receptors Interferon causes depression in 50% of patients Anti-TNF drug effective for depression with elevated baseline CRP but not low CRP

Intracellular Changes in Mood Disorders
Altered expression of multiple neuroplasticity/resilience genes Gene induction P53 Pro-apoptosis; tumor suppressor GSK-3ß Regulates cytoskeleton Phosphorylates and translocates proteins that promote neuronal death Slide 1

Intracellular Changes in Mood Disorders
Down-regulation of Bcl-2 cytoprotective stabilizes mitochondrial membranes anti-apoptotic Neuroplasticity/resilience factors Brain derived neurotrophic factor (BDNF) Increased by antidepressants Slide 2

Network Dysfunction in Depression
Hyperactivity in Amygdala Subgenual cingulate cortex (Cg25) Nucleus accumbens (striatum; reward and hedonic tone) Increased activity in default mode network (DMN) Ventromedial prefrontal cortex, posterior cingulate cortex and inferior parietal lobe Focused on internal events Self-referential thought Thinking about one’s past Inability to detach from depressive thinking and perception Overrides externally focused networks (task-focused networks) Respond to context-appropriate events Salience network (SN) Dorsal anterior cingulate cortex and insula Central executive network (CEN) Lateral frontal and parietal regions

Mind-Body Interactions
All cases of depression have mental and physical dimensions One feature may be more or less prominent in a given patient The same psychological event is more likely to produce depression in people with vulnerable stress response systems caused by Genetic factors Effects of illness/medications/substances Previous experience

Psychological Etiologies
Reaction to loss Mourning vs melancholia Loss precedes depression in 15% Loss produces depression in primates Similar physiologic changes Childhood loss of a parent best psychosocial predictor of adult depression Anger turned inward However, many depressed patients are openly angry Slide 1

Interpersonal theory Unresolved grief Disputes about roles and responsibilities Transitions to new roles Deficits in social skills Slide 2

Cognitive theory Global negative assumptions (schemata) Negative cognitions Catastrophic thinking Self-fulfilling prophecies Slide 3

Negative Schemata and Cognitions
If something isn’t done perfectly it’s worthless If I’m not perfect I’m a failure If everyone doesn’t love me unconditionally, no one loves me at all Negative cognitions: I’m no good I can’t do anything right Nobody loves me

Learned helplessness Behavioral theories Loss of reward for positive behaviors Reward of negative behaviors Slide 4

Importance of Psychological Factors
Most common psychological features Unresolved grief Helplessness Negative expectations, all-or-nothing thinking Difficulty expressing anger It does not matter whether psychological factors are cause or effect They interfere with treatment adherence Treating them improves medication response Antidepressants can reverse negative thinking and feeling overwhelmed

Risk of Chronicity At episode onset: 10%-15%
After 6 months of depression: 30%-40% After 1 year: 50% After 2 years: 95%

Risk of Recurrence After first episode: >50%
After second episode: >70% After third episode: >80% After fourth episode: >90%

Evolution of Unipolar Mood Disorders
Chronicity Recurrence Substance Use Character traits

Questions to Ask Before Prescribing an Antidepressant
What is the risk of suicide? How severe is the depression? Is there any evidence of bipolar depression? Which medications have/have not worked in the past? Which medications were/were not useful for close relatives? What are the patient’s feelings about taking medication? Is there a need for psychotherapy?

Factors that Increase the Risk of Suicide
High levels of hopelessness or anxiety Presence of a plan that can be carried out Rehearsal of the plan Psychotic or bipolar depression Lack of supports or other factors that would prevent the plan from being carried out Previous attempts, especially if severe Family history of suicide

Patients who Jumped from the Golden Gate Bridge
Ken Baldwin: “I wanted to disappear…I’d heard that the water just sweeps you under…[As soon as I jumped] I realized that everything in my life that I’d thought was unfixable was totally fixable- except for having just jumped” Kevin Hines: “I was, like, ‘fuck this, nobody cares. So I jumped. My first thought was ‘what the hell did I just do? I don’t want to die.” 26-year follow-up of 515 people prevented from jumping between 1937 and 1971 94% were still alive or had died of natural causes Chance of actual suicide diminished substantially after 90 days Seiden, 1978: Where are They Now?

Treatment

Treatments for Depression
Psychotherapy = pharmacotherapy for mild-moderate depression Pharmacotherapy > psychotherapy for severe, psychotic and bipolar depression Combined treatment necessary for chronic or complicated depression Overlapping target symptoms for pharmacotherapy and psychotherapy

Neurotransmitter Reuptake Inhibition
- AD

Problems with Reuptake Inhibition Theory
Reuptake inhibition is immediate but antidepressant effect takes a month or more Some antidepressants (e.g., mirtazepine, ECT) have no effect on neurotransmitter reuptake Neurotransmitter precursors are weak antidepressants Tianeptine is a serotonin reuptake enhancer Effects on gene expression probably more relevant to therapeutic effect Increased BDNF Neurotransmitter reuptake does predict side effects

Some Antidepressant Actions
Down-regulation of TNF-α Neurotransmitters, receptors; all antagonize NMDARs BDNF Neuronal viability Antidepressant Bcl-2 Neuroprotective Up-regulation of resilience genes ↓NO ↓ROS Antioxidant Histone acetylation Down-regulation of susceptibility genes Down-regulation of histone deacetylase Increased glial cell function Wnt Down-regulation of GSK-3β Enhanced synaptic function JM Launay et al: Translational Psychiatry 2011;1, e56; doi: /tp ; M. Schroeder et al: Clin Pharmacol Ther 2012;91:310; Voletti and Duman: Clin Pharmacol Ther 2012;91:333 B Di Benedetto et al: Current Drug Targets 2013;14:1329

Tricyclic Antidepressants
NE and 5HT reuptake inhibitors Tertiary amines (e.g., amitriptyline) inhibit reuptake of both Secondary amines (e.g., nortriptyline) inhibit norepinephrine reuptake No longer first line treatments Side effects Anticholinergic Postural hypotension Heart block Weight gain Possible increased risk of sudden death after MI LD50 = 1 week supply

Some Commonly Used TCAs
Generic Name Trade Name Uses Amitriptyline Elavil Migraines Chronic pain Nortriptyline Pamelor Refractory depression migraines Imipramine Tofranil Enuresis Separation anxiety Desipramine Norpramin Refractory depression Clomipramine Anafranil OCD

When to Use a TCA Depression refractory to other treatments
Past history of exclusive response to TCA Intractable migraines Chronic pain Ventricular ectopy with intolerance of type Ia antiarrhythmics Low risk of overdose

Serotonin Reuptake Inhibition
5HT1 5HT2 5HT3 5HT - SSRI

SSRIs Ease of use makes them first line treatments
All have similar efficacy and side effects Risky during pregnancy May improve vascular function and decrease inflammatory markers in CHD Preparations differ in elimination half-life and CYP450 inhibition Fluoxetine (Prozac): 3 days; 2D6; long-acting metabolite, activating Sertraline (Zoloft): 1 day; minimal 2D6 Paroxetine (Paxil): 1 day; 2D6; more weight gain; anticholinergic Fluvoxamine (Lexapro): <1 day; 3A4; BID dosing Citalopram (Celexa): 1 day; minimal P450; don’t use >40 mg/day Escitalopram (Lexapro): S-enantomer of citalopram; currently recommended at half the dose of citalopram; the only SSRI not available as generic

Common SSRI Side Effects
Sexual dysfunction Aggravation or improvement of migraine headaches Diarrhea, abdominal cramps Weight loss/gain Sedation/activation Withdrawal with paroxetine Antidopaminergic effect

Serotonin-Dopamine Interactions
5HT 5HT3 5HT2 + - DA

Consequences of Antidopaminergic Effect of SSRIs
Emotional blunting Decreased motivation and activity Memory loss Akathisia EPS Tardive dyskinesia (very rare)

5HT2 Receptors 5HT3 5HT 5HT2 5HT4 5HT1A Psychosis Anxiety Depression
Vasomotor Tone Interaction with D2 receptors to increase EPS

Trazodone (Deseryl) 5HT2 antagonist Elimination half-life 5-8 hours
Requires divided dose as antidepressant Useful as sleeping pill Sedation common May reduce SSRI sexual dysfunction Risk of priapism 1:6000 Impotence: 1:10,000

Nefazodone (Serzone) SRI and 5HT2 antagonist
Does not suppress REM sleep May improve sleep architecture Short half life requires divided dose as antidepressant Useful for fibromyalgia, chronic pain, sleep disorders Anxiogenic metabolite Hepatotoxicity in 18/10,000,000 with brand name Available only as generic

Bupropion (Welbutrin)
Dopamine and norepinephrine reuptake inhibitor No sexual or cardiac side effects Useful for sexual dysfunction caused by SSRIs First choice for patients with Parkinson's disease May be helpful for ADD and dementia Risk of seizures at doses >450 mg/day

Venlafaxine (Effexor)
Multiple neurotransmitter uptake inhibition 5HT at low doses NE at moderate doses DA at high doses Useful for severe and refractory depression May be useful for chronic pain XR form most commonly used Higher doses still must be divided Common side effects: Sedation Sexual dysfunction Hypertension at higher doses Withdrawal syndromes

Desvenlafaxine (Pristiq)
Metabolite of venlafaxine Blocks reuptake of NE, 5HT, DA Elimination half-life 9-10 hours Study that led to approval: mg/day Excluded patients with suicidality, bipolarity, other Axis I or medical/neurological illnesses Baseline HRSD 25 HRSD decreased to 12: DV 200 mg 13: DV 400 mg 16: Placebo Same side effects as venlafaxine No advantage over other antidepressants except to manufacturer Septien-Velez L et al: Int Clin Psychopharmacol 2007;22:

Mirtazepine (Remeron)
5HT2, 5HT3, α2 antagonist Useful for patients with Weight loss Nausea Sleep disorder Common side effects: Weight gain Sedation

Duloxetine (Cymbalta)
Norepinephrine and serotonin reuptake inhibitor Well tolerated BID dosing Not as much research as venlafaxine May improve chronic pain Causes nausea, sexual dysfunction and other 5HT/NE side effects Hypertension unlikely

Monoamine Oxidase Inhibitors
Useful for refractory, bipolar and atypical depression Usually prescribed by psychiatrists Cannot be combined with new antidepressants

NMDA Antagonists 12 RCTs of ketamine as augmentation of antidepressants or ECT 11 studies IV, 1 intranasal Ketamine alone produced antidepressant effect Starts in 2 hours; peaks within 1 day O.R. for response 9.87 Ketamine alone O.R. for response 7.55 3 studies report decrease in suicidal ideation within minutes-24 hours with ketamine Response lasted up to 2 weeks <1 week in bipolar depression with augmentation of mood stabilizer No significant effect of intranasal ketamine Psychotic and dissociative side effects Ketamine maintenance 3 days/week at lower dose ketamine for 2 weeks Sustained response for 3 weeks after end of treatment One patient had sustained remission for 3 months Ketamine augmentation of ECT (5 studies) Ketamine used instead of or in addition to standard anesthetic Longer seizure Greater improvement after first ECT but not at end of course of ECT Response the same for ECT with and without ketamine Post-ECT disorientation and restlessness twice as common with ketamine More hypertension with ketamine Eliminated with addition of propofol JW Murrough: Clin Pharmacol Ther 2012;91:303; DJ Newport et al: Am J Psychiatry 2015;172:

Non-Pharmacologic Somatic Treatments
ECT Most effective treatment Fewest side effects rTMS Mild to moderate depression No long-term research Artificial bright light Effective for seasonal depression Deep brain stimulation Experimental treatment for very severe depression

Prescribing Antidepressants
Start with a low dose Have patient call before each dosage increase If no response at all in 2-4 weeks at therapeutic dose change antidepressant Wait up to 6-8 weeks for full therapeutic response Do not continue inadequately effective antidepressant Goal of treatment is to suppress all symptoms as completely as possible (remission rather than just response) There is no evidence of superiority of any antidepressant over the others

Continuation/Maintenance Treatment in Unipolar Depression
Continue therapeutic dose for 8-12 months after a single mild episode Continue antidepressant indefinitely after second or third recurrence or single severe episode of unipolar depression Requires continued monitoring of patient Reassess suicidal thinking regularly

Psychotherapies for Depression
Cognitive therapy Cognitive behavior therapy Interpersonal therapy Expressive psychotherapy No controlled studies Equivalent to antidepressants in milder depression Not as effective as antidepressants in severe depression First choice for childhood depression

When to Prescribe Psychotherapy
Uncomplicated depression in patient who does not want an antidepressant Severe depression Chronic depression Recurrent depression Depression that does not respond to two antidepressants Substance abuse Presence of prominent psychosocial factors, especially Unresolved grief Negative thinking Interpersonal problems

Take Home Points Unipolar depression is chronic and recurrent
50% recurrence risk after a single episode Greater risk of chronicity the longer depression has been present Biological markers that have been replicated in depression Hypercortisolemia Nonsuppressed dexamethasone suppression test Blunted TRH stimulation test Decreased REM latency, reduced slow wave sleep Volume loss in hippocampus Inflammation All are indications of a hyperactive stress response Slide 1

Take Home Points Neurotransmitter theories Receptor theories
Decreased NE, 5HT, ?DA Receptor theories Beta adrenergic and 5HT2 receptors Not clear if secondary to treatment or neurotransmitter changes Altered expression of genes for second messengers, BDNF and other neuroprotective proteins may be more relevant Inflammation may influence all of these Psychological factors are important, especially Grief Helplessness Negative thinking Slide 2

Take Home Points Unipolar depression is familial
Oligogenic inheritance Best predictors of risk of depression Childhood loss of a parent Family history of depression Most popular theory of antidepressant action involves inhibition of reuptake of NE and/or 5HT Intracellular actions are probably more important (e.g., induction of BDNF) but incompletely understood Slide 3

Take Home Points Any antidepressant has a 60% chance of working
With more aggressive treatment, response rates increase to 85-90% Remission rates are lower (40%) Know about antidepressant classes, ECT, artificial bright light, interpersonal therapy, cognitive therapy Goal of treatment is remission Continued treatment reduces risk of relapse (return of original episode) and recurrence (onset of a new episode) Slide 4

Unipolar Depression Steven L. Dubovsky, M.D..

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Unipolar Depression Steven L. Dubovsky, M.D..

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