Transcript Monoamine Hypothesis of Depression

Mood Disorder Categories (DSM-IV)
• Depressive disorders
– Major depressive disorder, clinical depression
– Dysthymia
– Depressive Disorder Not Otherwise Specified (NOS)
• Bipolar disorder
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Bipolar I
Bipolar II
Cyclothymic Disorder
Bipolar Disorder NOS
Changes from DSM-IV-TR to DSM-5
• Depressive Disorders contains new categories
– disruptive mood dysregulation disorder
• children up to age 18 years
• replaces bipolar disorder in children
– premenstrual dysphoric disorder
– persistent depressive disorder
• chronic major depressive disorder
• dysthymic disorder
• Major Depressive Disorder: changes to the organization of
categories
– bereavement exclusion removed
• Bipolar Disorders has more emphasis on changes in activity
and energy
– bipolar I disorder includes “with mixed features”
Prevalence of Depression
• Prevalence of major depressive disorder
– Higher in Whites than in African Americans and Mexican
Americans
– Opposite pattern was found for dysthymic disorder
• Chronic (two years) of mild depression
• Low energy, disturbances in sleep or in appetite, and
low self-esteem
• Poverty was a significant risk factor for major depressive
disorder and dysthymic disorder
• See Table 1 and Figure 1 on the following slides
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Prevalence of Depression by Race/Ethnicity: Findings From the National Health
and Nutrition Examination Survey III. American Journal of Public Health | June
2005, Vol 95, No. 6
Table 1 Prevalence of Depression
Figure 1 Prevalence of Depression
Symptoms of Clinical Depression
• Clinical symptoms common to depression include
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Pervasive unhappiness and despair
Negative, pessimistic thoughts
Anhedonia (inability to experience pleasure)
Loss of self-esteem
Impairment of normal functioning (home, social, work)
Suicidal ideas
• Vegetative symptoms that warrant medication treatment
(when seen with symptoms above)
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Appetite disturbance
Sleep disturbance (early am wakening, frequent awakenings)
Diurnal mood variation (worse in morning)
Marked anhedonia “inability to experience pleasure in normally
pleasurable acts”
Role of genetics in depression
• High concordance rates: (60%) in monozygotic twins
• High rates of mood disorder in family members
• No evidence of a single gene
– small associations between the polymorphism in the
serotonin transporter promoter region
– association of MDD with polymorphisms gene for
brain-derived neurotrophic factor (BDNF).
• related to recovery from stress
Table 16.3 Drugs Used to Treat Depression
Drugs Used To Treat Depression
Amine Depression Hypotheses
• Biogenic amine hypothesis suggests that depression reflects a
suboptimal level of NE, DA, EPI, or 5-HT in brain
– Reserpine depletes CNS catecholamines (leads to depression)
– Depressed patients have low levels of 5-HIAA (metabolite)
– drugs that block reuptake elevate synaptic levels of NE and 5-HT
(e.g. imipramine)
• Problems for the amine hypothesis
– Some drugs used to treat depression (bupropion) do not block
reuptake of amines
– Why doesn’t Cocaine reduce depression?
– Why doesn’t Ecstasy reduce depression?
– Why is there a temporal delay between drug administration, onset
of amine changes, and reduction in depression?
Role of Glutamate in Depression
• Too much glutamate can overstimulate neurons causing
collapse of the branches by which they communicate
with other cells
• One effect of antidepressants is to reduce the sensitivity
of receptors in the PFC for glutamate
• Antidepressant-like actions of compounds which reduce
transmission at N-methyl-D-aspartate (NMDA) receptors
• Towards a glutamate hypothesis of depression: an
emerging frontier of neuropsychopharmacology for mood
disorders. (2012) Sanacora G, Treccani G, Popoli M
Neuropharmacology. Jan;62(1):63-77.
Role of Glutamate in Depression
• Treating depression with Ketamine
– Blocking NMDA type of glutamate receptors
– A single dose of ketamine has rapid and lasting antidepressant
effects in patients with major depression or bipolar disorder.
– Zarate CA Jr. A randomized add-on trial of an N-methyl-Daspartate antagonist in treatment-resistant bipolar depression.
Arch Gen Psychiatry. 2010 Aug;67(8):793-802.
– Zarate CA Jr. Rapid resolution of suicidal ideation after a single
ketamine infusion in patients with treatment-resistant major
depression. J Clin Psychiatry, 71:1605-11, 2010.
Role of Stress in Depression
• Dysregulation of HPA : to much cortisol
• Damages hippocampus
– Changes the shape, size and number of
• Damages prefrontal cortex and the amygdala
– smaller in people with recurrent depression
• Suppressed nerve cell growth in a part of the
hippocampus
Diathesis-Stress Model
• Diathesis is vulnerability or susceptibility
– Genetic influences
• High concordance rate in twin studies
• family history of mental disorder
• hypothalamic-pituitary-adrenal responsivity
– Developmental
• maternal stressors
• childhood maltreatment
• Interaction of Diathesis and Stress
– Individuals with more vulnerability are more likely to
become ill when challenged by stressors
Treatments for depression
• Drug Therapy
• Monoamine oxidase (MAO)
• Tricyclic drugs
• Selective serotonin reuptake inhibitors (SSRIs)
• Ketamine and leptin
• Brain stimulation
• Deep brain stimulation (DBS)
• Vagal nerve stimulation
• Electroconvulsive shock therapy (ECT)
• Transcranial magnetic stimulation (TMS)
• Cognitive behavioral therapy (CBT)
Placebo Effect in Depression
Effectiveness of antidepressant drugs
– 50-60 % symptom free
– 20-30 % some improvement
– 20 % no improvement
Placebo effect: 30 – 50 % show improvement
Drug therapy plus Psychotherapy is most effective
treatment
The Treadmill of Depression
The Hypothalamic-Pituitary-Adrenal Axis in Depression
Brain Activity Patterns from PET scan in Depression
Increased activity in Prefrontal Cortex and Amygdala
Sleep and Depression
Light therapy for Seasonal affective disorder (SAD)
Gender Differences in Depression
• Major Depression
– Women twice as likely as men
– But girls and boys have equal rates
– Power Theory
• Higher levels of physical and psychological abuse
• Living in poverty
• Overburdened by family & work responsibilities
– Coping Style
• Women are more interpersonally oriented
• Respond to interpersonal stressors with rumination
• Men more likely to use alcohol to cover up symptoms
– Reactivity to Stress
• HPA response to stress dysregulated
• HPA modulated by estrogen levels
Bipolar disorder
• Characterized by periods of depression
alternating with expansive mood, or mania.
• The rate of cycling varies–rapid cycling consists
of four or more cycles in one year.
• Some individuals may cycle several times in one
day.
• In Cyclothymia–a milder form of bipolar
disorder–patients cycle between dysthymia (mild
depression) and hypomania (increased energy).
• Lithium is a mood-stabilizing drug used to treat
bipolar disorder.