Antidepressants and Treatment of Mood Disorders

Anita S. Kablinger M.D.

Associate Professor

Departments of Psychiatry and Pharmacology

Outline of Lecture

• Definitions

• DSM-IV diagnoses and criteria

• Epidemiology

• Neurobiology

• Psychosocial theories

• Treatments

Definitions

• Depression can refer to many things and mean different things to different people

• Symptom versus syndrome

• However, for a clinical depression consistent with DSM-IV, this must lead to functional impairment

DSM-IV Diagnostic Categories

• Major Depression• Dysthymia• Depressive Disorder

NOS• Bipolar Disorder,

Type I or II• Cyclothymia

• Bipolar Disorder NOS• Mood Disorder

secondary to GMC• Substance-Induced

Mood Disorder• Adjustment Disorder

(separate classification)

Epidemiology

• Depression is the most common cause of disability in the world

• U.S. costs approximate 43$ billion per year for mood disorders

• Lifetime prevalence rates: (according to NCS), 21-24% for women and 12-15% for men

Major Depressive Disorder (MDD)

• >2 week period of change in behavior with 5 of the following:– *depressed mood– *anhedonia– appetite disturbance– sleep disturbance– psychomotor

disturbance

– fatigue or loss of energy

– worthlessness or guilt

– impaired concentration

– suicidal thoughts

• * 1/5 symptoms must be these

• Rule out physical cause

Time Course of MDD

• Often lasts for a year without treatment

• Chances increase by 50% for another episode after current episode (i.e. high relapse and recurrence rates)

• Many go on to experience chronic depression (but may be a result of inadequate treatment)

Heritability of Mood Disorders

• Genetic factors very important

• RR of MDD is 2-5x greater in relatives of depressed patients than controls

• First degree relatives of Bipolar patients are 24x more likely to develop BAD than general population

• Twin and adoption studies help to understand and define this illness

Psychosocial Theories of Depression

• Risk factors include:– recent stressors– poor social support system– history of early parental loss– gender– family history of depression– negative cognitive style

Theories of Depression• NE and DA broken down to variety of products through

MAO and COMT• 5HT is broken down by MAO to 5-HIAA• Major mechanism for terminating signal is neuronal

reuptake • Monoaminergic Theories

– Reserpine (early antihypertensive)– Iproniazid (used to treat TB)– Imipramine (originally studied as an antipsychotic)– Drugs enhancing noradrenergic functioning were

antidepressants (eg. stimulants)

Indoleamine Hypothesis of Depression

• Serotonin is functionally deficient in depression– Decreased brain 5-HT and CSF 5-HIAA in

many depressed patients– Antidepressants tend to increase central

serotonin transmission– Depressed patients show reduction in 5-HT

reuptake sites– Blunted neuroendocrine challenges

Neurotransmitter Hypothesis of Mood Disorders

• Led to catecholamine hypothesis– NE ↓ in depression and in mania– 5-HT ↓ production or reuptake in depression

• Flaws: depression or mania not reliably produced and clinical response exceeds mechanism of action of drug

Neurobiology of Mood Disorders

• Neuroendocrine abnormalities: reflect central neurotransmitter dysfunction– hyperactivity of HPA: increased cortisol,

nonsuppression of cortisol in DST– blunting of TSH release following TRH infusion– blunting of GH release with alpha-2 adrenergic

agonism and serotonin-mediated increases in prolactin

Other Alterations in Depression

– CRH– acetylcholine activity– GABA levels– Excessive glucocorticoid activity in psychotic

depression– Hippocampal volume loss

Neurobiology of Mood Disorders

• Sleep abnormalities: usually found in endogenous depression– prolonged sleep latency– shortened REM latency and change in timing– increased wakefulness– decreased arousal threshold– early morning awakening– reduced stage 3 and 4 sleep

Kindling-Sensitization Hypothesis of Mood Disorders

• Suggests that repeated exposure to stress and/or neurochemical changes during depressed episode sensitize brain regions responsible for affect

• Repeated episodes may permanently alter systems within the CNS

• Leads to shorter well periods, increased frequency and severity of illness

Treatments

• Pharmacotherapy

• Psychotherapy

• Social interventions

• ECT

• TMS

• VNS

Which Medication?

• Safety

• Tolerability

• Efficacy

• Payment

• Simplicity

Available Types of Pharmacotherapy

• Tricyclic antidepressants (TCA)

• MAOI’s

• SSRI’s

• SNRI’s

• Atypical antidepressants

• Mood stabilizers

• Antipsychotics

General Treatment Rules

• Often takes 4-6 weeks for response• Monitor for response versus remission• Vegetative symptoms tend to improve first,

cognitive symptoms take longer• SSRI’s are the first line of treatment for most

MDD’s• Address biopsychosocial needs and maintain

meds for 6-12 months

Tricyclic Antidepressants

• Available for more than 30 years

• Cheap but not clean

• Act by NE and/or 5 HT presynaptic reuptake inhibition

• Side effects include anticholinergic effects, orthostasis, slowing of cardiac conduction

• Secondary better than tertiary compounds

Selective Serotonin Reuptake Inhibitors

• Produce response rates close to 70%

• Safer and better tolerated than TCA’s

• Given once daily

• Starting and therapeutic doses often similar

• Most common side effects include GI symptoms, HA, insomnia, anxiety, and sexual dysfunction

• Five available in the U.S.

Novel or Atypical Antidepressants

• Bupropion (NE and DA reuptake inhibition)

• Trazodone (5 HT2 alpha-ANT)

• Venlafaxine and Duloxetine (NE and 5 HT reuptake blockers – SNRI’s)

• Mirtazapine (presynaptic alpha 2 ANT and 5 HT2 and 5 HT3 ANT)

Psychotherapy in Depression

• Supportive

• Insight-oriented

• Interpersonal

• Cognitive-behavioral

• Psychodynamic

• Individual, group or family